Oligonucleotides for inducing paternal UBE3A expression

ABSTRACT

The present invention relates to oligonucleotides that are capable of inducing expression of ubiquitin-protein ligase E3A (UBE3A) from the paternal allele in animal or human neurons. The oligonucleotides target the suppressor of the UBE3A paternal allele by hybridization to SNHG14 long non-coding RNA downstream of SNORD109B. The present invention further relates to pharmaceutical compositions and methods for treatment of Angelman syndrome.

PRIORITY INFORMATION

This application is a continuation and claims priority toPCT/EP2016/077383, filed Nov. 11, 2016, which claims priority toEP15194367.7, filed Nov. 12, 2015 and EP161895024, filed Sep. 19, 2016.The contents of which are hereby incorporated by reference.

FIELD OF INVENTION

The present invention relates to oligonucleotides (oligomers) that arecomplementary to and hybridize to SNHG14 downstream of SNORD109B,leading to induction of paternal expression of Ubiquitin-protein ligaseE3A (UBE3A) in an animal or human. The present invention further relatesto pharmaceutical compositions and methods for treatment of Angelmansyndrome.

BACKGROUND

Angelman syndrome is neuro-genetic disorder caused by deletion orinactivation of the UBE3A genes on the maternally inherited chromosome15q11.2. The paternal copy of the UBE3A gene is subject to genomicimprinting and silencing in neurons by an endogenous antisensetranscript of UBE3A, termed SNHG14 (also known as UBE3A-ATS) (Meng etal. 2012 Hum Mol Genet. Vol. 21 pp. 3001-12). Other cell types thanneurons seem to express the UBE3A gene from both the maternal andpaternal allele.

Angelman syndrome is characterized by severe intellectual anddevelopmental disability, sleep disturbance, seizures, jerky movements,EEG abnormalities, frequent laughter or smiling, and profound languageimpairments.

WO 2012/064806 discloses a method of inducing UBE3A expression in a cellby using a topoisomerase inhibitor. The method can be used to treatAngelman syndrome. There is no disclosure of antisense oligonucleotides.

WO 2014/004572 discloses oligonucleotides with 2′-O-methoxyethyl-RNA(MOE) modifications targeting mouse UBE3A-ATS. The oligonucleotides areonly tested in mice related assays. In the region downstream of MBII-52snoRNA (also known as SNORD115) and upstream of the UBE3A pre-mRNA thereis no conservation between mouse and human. Oligonucleotides targetingmouse UBE3A-ATS can therefore not be translated into oligonucleotidesthat will function in a human. There is no disclosure ofoligonucleotides targeting human UBE3A-ATS.

OBJECTIVE OF THE INVENTION

The present invention identifies novel oligonucleotides which inducehuman paternal UBE3A expression in neuronal without affection expressionof the paternal SNORD115, SNORD116 and SNRPN transcripts significantly.

SUMMARY OF INVENTION

The present invention relates to oligonucleotides targeting a nucleicacid capable of suppressing the expression of UBE3A and to treat orprevent diseases related to decreased activity of UBE3A, in particularin neuronal cells.

Accordingly, in a first aspect the invention provides oligonucleotideswhich comprise a contiguous nucleotide sequence of 10 to 30 nucleotidesin length with at least 98% complementarity to the part of human SNHG14long non-coding RNA corresponding to position 25278410 to 25419462 onhuman chromosome 15 version GRCh38.p2. This region is also resembled bySEQ ID NO: 1. The oligonucleotide can be an antisense oligonucleotide,preferably with a gapmer design. Preferably, the oligonucleotide iscapable of inducing the expression of UBE3A, in particular paternalUBE3A expression in a neuron, by degradation, reduction or removal ofthe UBE3A suppressor, in particular by reduction of the SNHG14 longnon-coding RNA transcript downstream of SNORD109B. The UBE3Are-expression is achieved, without significantly affecting theexpression of SNORD115. The degradation of the target nucleic acid ispreferably achieved via nuclease recruitment.

In a further aspect, the invention provides pharmaceutical compositionscomprising the oligonucleotides of the invention and pharmaceuticallyacceptable diluents, carriers, salts and/or adjuvants.

In a further aspect, the invention provides methods for in vivo or invitro induction of UBE3A expression in a target cell where expression ofpaternal UBE3A is suppressed, by administering an oligonucleotide orcomposition of the invention in an effective amount to said cell.

In a further aspect the invention provides methods for treating orpreventing a disease, disorder or dysfunction associated with in vivoactivity of UBE3A comprising administering a therapeutically orprophylactically effective amount of the oligonucleotide of theinvention to a subject suffering from or susceptible to the disease,disorder or dysfunction.

In a further aspect the oligonucleotide or composition of the inventionis used for the treatment or prevention of Angelman syndrome.

BRIEF DESCRIPTION OF FIGURES

FIG. 1: The upper strand illustrates the region of the SNHG14 transcriptdownstream of SNORD109B (UBE3A-ATS) where the black boxes indicate thelocation of the tested mouse oligonucleotides. The lower strandillustrates the UBE3A coding region, where the black boxes indicateexons. Exon 1 is located around 160 kb. The oligonucleotides are placedin the antisense region of Exon 9 (positioned at ˜97 kb), Exon 10(positioned at ˜92 kb), Exon 13 (positioned at ˜77 kb) and the 5′ end ofExon 16 (positioned at ˜60 kb).

FIG. 2: Representation of the ability of the oligonucleotides, tested inExample 2, to induce re-expression of UBE3A in human neuronal cellcultures. Oligonucleotides complementary to the region of human SNHG14long non-coding RNA between SNORD109B and the region upstream of theUBE3A coding region (position 1 to 55318 of SEQ ID NO: 1) are indicatedwith ● nonoverlap. Oligonucleotides complementary to the region of humanSNHG14 long non-coding RNA which is antisense to the UBE3A pre-mRNA(position 55319 to 141053 of SEQ ID NO: 1) are indicated with ▴ overlap.Oligonucleotides from Table 3 with conservation to human and rhesusmonkey are indicated at the bottom of each plot as

. Conservation between human:rhesus:mouse is indicated by

. The oligonucleotide concentrations were 0.2, 1 and 5 microM asindicated in the right hand side each plot.

DEFINITIONS

Oligonucleotide

The term “oligonucleotide” as used herein is defined as it is generallyunderstood by the skilled person as a molecule comprising two or morecovalently linked nucleosides. Such covalently bound nucleosides mayalso be referred to as nucleic acid molecules or oligomers.Oligonucleotides are commonly made in the laboratory by solid-phasechemical synthesis followed by purification. When referring to asequence of the oligonucleotide, reference is made to the sequence ororder of nucleobase moieties, or modifications thereof, of thecovalently linked nucleotides or nucleosides. The oligonucleotide of theinvention is man-made, and is chemically synthesized, and is typicallypurified or isolated. The oligonucleotide of the invention may compriseone or more modified nucleosides or nucleotides.

Antisense Oligonucleotides

The term “Antisense oligonucleotide” as used herein is defined asoligonucleotides capable of modulating expression of a target gene byhybridizing to a target nucleic acid, in particular to a contiguoussequence on a target nucleic acid. The antisense oligonucleotides arenot essentially double stranded and are therefore not siRNAs.Preferably, the antisense oligonucleotides of the present invention aresingle stranded.

Contiguous Nucleotide Sequence

The term “contiguous nucleotide sequence” refers to the region of theoligonucleotide which is complementary to the target nucleic acid. Theterm is used interchangeably herein with the term “contiguous nucleobasesequence” and the term “oligonucleotide motif sequence”. In someembodiments all the nucleotides of the oligonucleotide are present inthe contiguous nucleotide sequence. In some embodiments theoligonucleotide comprises the contiguous nucleotide sequence and may,optionally comprise further nucleotide(s), for example a nucleotidelinker region which may be used to attach a functional group to thecontiguous nucleotide sequence. The nucleotide linker region may or maynot be complementary to the target nucleic acid.

Nucleotides

Nucleotides are the building blocks of oligonucleotides andpolynucleotides, and for the purposes of the present invention includeboth naturally occurring and non-naturally occurring nucleotides. Innature, nucleotides, such as DNA and RNA nucleotides comprise a ribosesugar moiety, a nucleobase moiety and one or more phosphate groups(which is absent in nucleosides). Nucleosides and nucleotides may alsointerchangeably be referred to as “units” or “monomers”.

Modified Nucleoside

The term “modified nucleoside” or “nucleoside modification” as usedherein refers to nucleosides modified as compared to the equivalent DNAor RNA nucleoside by the introduction of one or more modifications ofthe sugar moiety or the (nucleo)base moiety. In a preferred embodimentthe modified nucleoside comprises a modified sugar moiety. The termmodified nucleoside may also be used herein interchangeably with theterm “nucleoside analogue” or modified “units” or modified “monomers”.

Modified Internucleoside Linkage

The term “modified internucleoside linkage” is defined as generallyunderstood by the skilled person as linkages other than phosphodiester(PO) linkages, that covalently couples two nucleosides together.Nucleotides with modified internucleoside linkage are also termed“modified nucleotides”. In some embodiments, the modifiedinternucleoside linkage increases the nuclease resistance of theoligonucleotide compared to a phosphodiester linkage. For naturallyoccurring oligonucleotides, the internucleoside linkage includesphosphate groups creating a phosphodiester bond between adjacentnucleosides. Modified internucleoside linkages are particularly usefulin stabilizing oligonucleotides for in vivo use, and may serve toprotect against nuclease cleavage at regions of DNA or RNA nucleosidesin the oligonucleotide of the invention, for example within the gapregion of a gapmer oligonucleotide, as well as in regions of modifiednucleosides.

In an embodiment, the oligonucleotide comprises one or moreinternucleoside linkages modified from the natural phosphodiester to alinkage that is for example more resistant to nuclease attack. Nucleaseresistance may be determined by incubating the oligonucleotide in bloodserum or by using a nuclease resistance assay (e.g. snake venomphosphodiesterase (SVPD)), both are well known in the art.Internucleoside linkages which are capable of enhancing the nucleaseresistance of an oligonucleotide are referred to as nuclease resistantinternucleoside linkages. In preferred embodiments at least 50% of theinternucleoside linkages in the oligonucleotide, or contiguousnucleotide sequence thereof, are modified, such as at least 60%, such asat least 70%, such as at least 80 or such as at least 90% of theinternucleoside linkages in the oligonucleotide, or contiguousnucleotide sequence thereof, are modified. In some embodiments all ofthe internucleoside linkages of the oligonucleotide, or contiguousnucleotide sequence thereof, are modified. It will be recognized that,in some embodiments the nucleosides which link the oligonucleotide ofthe invention to a non-nucleotide functional group, such as a conjugate,may be phosphodiester. In some embodiments all of the internucleosidelinkages of the oligonucleotide, or contiguous nucleotide sequencethereof, are nuclease resistant internucleoside linkages.

Modified internucleoside linkages may be selected from the groupcomprising phosphorothioate, diphosphorothioate and boranophosphate. Inpreferred embodiments, the modified internucleoside linkages arecompatible with the RNaseH recruitment of the oligonucleotide of theinvention, for example phosphorothioate, diphosphorothioate orboranophosphate.

In some embodiments the internucleoside linkage comprises sulphur (S),such as a phosphorothioate internucleoside linkage.

A phosphorothioate internucleoside linkage is particularly useful due tonuclease resistance, beneficial pharmakokinetics and ease ofmanufacture. In preferred embodiments at least 50% of theinternucleoside linkages in the oligonucleotide, or contiguousnucleotide sequence thereof, are phosphorothioate, such as at least 60%,such as at least 70%, such as at least 80 or such as at least 90% of theinternucleoside linkages in the oligonucleotide, or contiguousnucleotide sequence thereof, are phosphorothioate. In some embodimentsall of the internucleoside linkages of the oligonucleotide, orcontiguous nucleotide sequence thereof, are phosphorothioate.

In some embodiments, the oligonucleotide comprises one or more neutralinternucleoside linkage, particularly a internucleoside linkage selectedfrom phosphotriester, methylphosphonate, MMI, amide-3, formacetal orthioformacetal.

Further internucleoside linkages are disclosed in WO2009/124238(incorporated herein by reference). In an embodiment the internucleosidelinkage is selected from linkers disclosed in WO2007/031091(incorporated herein by reference). Particularly, the internucleosidelinkage may be selected from —O—P(O)₂—O—, —O—P(O,S)—O—, —O—P(S)₂—O—,—S—P(O)₂—O—, —S—P(O,S)—O—, —S—P(S)₂—O—, —O—P(O)₂—S—, —O—P(O,S)—S—,—S—P(O)₂—S—, —O—PO(R^(H))—O—, O—PO(OCH₃)—O—, —O—PO(NR^(H))—O—,—O—PO(OCH₂CH₂S—R)—O—, —O—PO(BH₃)—O—, —O—PO(NHR^(H))—O—,—O—P(O)₂—NR^(H)—, —NR^(H)—P(O)₂—O—, —NR^(H)—CO—O—, —NR^(H)—CO—NR^(H)—,and/or the internucleoside linker may be selected form the groupconsisting of: —O—CO—O—, —O—CO—NR^(H)—, —NR^(H)—CO—CH₂—,—O—CH₂—CO—NR^(H)—, —O—CH₂—CH₂—NR^(H)—, CO—NR^(H)—CH₂—, —CH₂—NR^(H)CO—,—O—CH₂—CH₂—S—, —S—CH₂—CH₂—O—, —S—CH₂—CH₂—S—, —CH₂—SO₂—CH₂—,—CH₂—CO—NR^(H)—, —O—CH₂—CH₂—NR^(H)—CO—, —CH₂—NCH₃—O—CH₂—, where R^(H) isselected from hydrogen and C1-4-alkyl.

Nuclease resistant linkages, such as phosphothioate linkages, areparticularly useful in oligonucleotide regions capable of recruitingnuclease when forming a duplex with the target nucleic acid, such asregion G for gapmers, or the non-modified nucleoside region of headmersand tailmers. Phosphorothioate linkages may, however, also be useful innon-nuclease recruiting regions and/or affinity enhancing regions suchas regions F and F′ for gapmers, or the modified nucleoside region ofheadmers and tailmers.

Each of the design regions may however comprise internucleoside linkagesother than phosphorothioate, such as phosphodiester linkages, inparticularly in regions where modified nucleosides, such as LNA, protectthe linkage against nuclease degradation. Inclusion of phosphodiesterlinkages, such as one or two linkages, particularly between or adjacentto modified nucleoside units (typically in the non-nuclease recruitingregions) can modify the bioavailability and/or bio-distribution of anoligonucleotide—see WO2008/113832, incorporated herein by reference.

In an embodiment all the internucleoside linkages in the oligonucleotideare phosphorothioate and/or boranophosphate linkages. Preferably, allthe internucleoside linkages in the oligonucleotide are phosphorothioatelinkages.

Nucleobase

The term nucleobase includes the purine (e.g. adenine and guanine) andpyrimidine (e.g. uracil, thymine and cytosine) moiety present innucleosides and nucleotides which form hydrogen bonds in nucleic acidhybridization. In the context of the present invention the termnucleobase also encompasses modified nucleobases which may differ fromnaturally occurring nucleobases, but are functional during nucleic acidhybridization. In this context “nucleobase” refers to both naturallyoccurring nucleobases such as adenine, guanine, cytosine, thymidine,uracil, xanthine and hypoxanthine, as well as non-naturally occurringvariants. Such variants are for example described in Hirao et al (2012)Accounts of Chemical Research vol 45 page 2055 and Bergstrom (2009)Current Protocols in Nucleic Acid Chemistry Suppl. 37 1.4.1.

In a some embodiments the nucleobase moiety is modified by changing thepurine or pyrimidine into a modified purine or pyrimidine, such assubstituted purine or substituted pyrimidine, such as a nucleobasedselected from isocytosine, pseudoisocytosine, 5-methyl cytosine,5-thiozolo-cytosine, 5-propynyl-cytosine, 5-propynyl-uracil,5-bromouracil 5-thiazolo-uracil, 2-thio-uracil, 2′thio-thymine, inosine,diaminopurine, 6-aminopurine, 2-aminopurine, 2,6-diaminopurine and2-chloro-6-aminopurine.

The nucleobase moieties may be indicated by the letter code for eachcorresponding nucleobase, e.g. A, T, G, C or U, wherein each letter mayoptionally include modified nucleobases of equivalent function. Forexample, in the exemplified oligonucleotides, the nucleobase moietiesare selected from A, T, G, C, and 5-methyl cytosine. Optionally, for LNAgapmers, 5-methyl cytosine LNA nucleosides may be used.

Modified Oligonucleotide

The term modified oligonucleotide describes an oligonucleotidecomprising one or more sugar-modified nucleosides and/or modifiedinternucleoside linkages. The term chimeric” oligonucleotide is a termthat has been used in the literature to describe oligonucleotides withmodified nucleosides.

Complementarity

The term complementarity describes the capacity for Watson-Crickbase-pairing of nucleosides/nucleotides. Watson-Crick base pairs areguanine (G)-cytosine (C) and adenine (A)-thymine (T)/uracil (U). It willbe understood that oligonucleotides may comprise nucleosides withmodified nucleobases, for example 5-methyl cytosine is often used inplace of cytosine, and as such the term complementarity encompassesWatson Crick base-paring between non-modified and modified nucleobases(see for example Hirao et al (2012) Accounts of Chemical Research vol 45page 2055 and Bergstrom (2009) Current Protocols in Nucleic AcidChemistry Suppl. 37 1.4.1).

The term “% complementary” as used herein, refers to the number ofnucleotides in percent of a contiguous nucleotide sequence in a nucleicacid molecule (e.g. oligonucleotide) which, at a given position, arecomplementary to (i.e. form Watson Crick base pairs with) a contiguousnucleotide sequence, at a given position of a separate nucleic acidmolecule (e.g. the target nucleic acid). The percentage is calculated bycounting the number of aligned bases that form pairs between the twosequences, dividing by the total number of nucleotides in theoligonucleotide and multiplying by 100. In such a comparison anucleobase/nucleotide which does not align (form a base pair) is termeda mismatch.

The term “fully complementary”, refers to 100% complementarity.

Hybridization

The term “hybridizing” or “hybridizes” as used herein is to beunderstood as two nucleic acid strands (e.g. an oligonucleotide and atarget nucleic acid) forming hydrogen bonds between base pairs onopposite strands thereby forming a duplex. The affinity of the bindingbetween two nucleic acid strands is the strength of the hybridization.It is often described in terms of the melting temperature (T_(m))defined as the temperature at which half of the oligonucleotides areduplexed with the target nucleic acid. At physiological conditions T_(m)is not strictly proportional to the affinity (Mergny and Lacroix, 2003,Oligonucleotides 13:515-537). The standard state Gibbs free energy ΔG°is a more accurate representation of binding affinity and is related tothe dissociation constant (K_(d)) of the reaction by ΔG°=−RTln(K_(d)),where R is the gas constant and T is the absolute temperature.Therefore, a very low ΔG° of the reaction between an oligonucleotide andthe target nucleic acid reflects a strong hybridization between theoligonucleotide and target nucleic acid. ΔG° is the energy associatedwith a reaction where aqueous concentrations are 1M, the pH is 7, andthe temperature is 37° C. The hybridization of oligonucleotides to atarget nucleic acid is a spontaneous reaction and for spontaneousreactions ΔG° is less than zero. ΔG° can be measured experimentally, forexample, by use of the isothermal titration calorimetry (ITC) method asdescribed in Hansen et al., 1965, Chem. Comm. 36-38 and Holdgate et al.,2005, Drug Discov Today. The skilled person will know that commercialequipment is available for ΔG° measurements. ΔG° can also be estimatednumerically by using the nearest neighbor model as described bySantaLucia, 1998, Proc Natl Acad Sci USA. 95: 1460-1465 usingappropriately derived thermodynamic parameters described by Sugimoto etal., 1995, Biochemistry 34:11211-11216 and McTigue et al., 2004,Biochemistry 43:5388-5405. In order to have the possibility ofmodulating its intended nucleic acid target by hybridization,oligonucleotides of the present invention hybridize to a target nucleicacid with estimated ΔG° values below −10 kcal for oligonucleotides thatare 10-30 nucleotides in length. In some embodiments the degree orstrength of hybridization is measured by the standard state Gibbs freeenergy ΔG°. The oligonucleotides may hybridize to a target nucleic acidwith estimated ΔG° values below the range of −10 kcal, such as below −15kcal, such as below −20 kcal and such as below −25 kcal foroligonucleotides that are 8-30 nucleotides in length. In someembodiments the oligonucleotides hybridize to a target nucleic acid withan estimated ΔG° value of −10 to −60 kcal, such as −12 to −40, such asfrom −15 to −30 kcal or −16 to −27 kcal such as −18 to −25 kcal.

The Target

The target refers to the protein which it is desired to modulate.

Target Nucleic Acid

A target nucleic acid is the intended target which the oligonucleotideof the invention hybridizes to, and may for example be a gene, a RNA, anon-coding RNA, a long non-coding RNA, a mRNA, and pre-mRNA, a maturemRNA or a cDNA sequence. In some embodiments the target nucleic acid isa non-coding RNA or a long non-coding RNA, or a subsequence thereof. Forin vivo or in vitro application, the oligonucleotide of the invention iscapable of decreasing the level of the SNHG14 transcript downstream ofSNORD109B of and thereby relieving the suppression of the paternal UBE3Atranscript in the intended target cell. The contiguous sequence ofnucleobases of the oligonucleotide of the invention is complementary tothe target nucleic acid, as measured across the length of theoligonucleotide, optionally with the exception of one or two mismatches,and optionally excluding nucleotide based linker regions which may linkthe oligonucleotide to an optional functional group such as a conjugate.

Target Sequence

The oligonucleotide comprises a contiguous nucleotide sequence which iscomplementary to or hybridizes to a sub-sequence of the target nucleicacid molecule. The term “target sequence” as used herein refers to asequence of nucleotides present in the target nucleic acid whichcomprises the nucleobase sequence which is complementary to theoligonucleotide of the invention. In some embodiments, the targetsequence consists of a region on the target nucleic acid which iscomplementary to the contiguous nucleotide sequence of theoligonucleotide of the invention. In some embodiments the targetsequence is longer than the complementary sequence of a singleoligonucleotide, and may, for example represent a preferred region ofthe target nucleic acid which may be targeted by severaloligonucleotides of the invention.

The oligonucleotide of the invention comprises a contiguous nucleotidesequence which is complementary to the target nucleic acid, such as atarget sequence.

The oligonucleotide comprises a contiguous nucleotide sequence of atleast 8 nucleotides which is complementary to or hybridizes to a targetsequence present in the target nucleic acid molecule. The contiguousnucleotide sequence (and therefore the target sequence) comprises of atleast 8 contiguous nucleotides, such as 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 contiguousnucleotides, such as from 12-25, such as from 14-18 contiguousnucleotides.

Target Cell

The term a target cell as used herein refers to a cell which isexpressing the target nucleic acid. In some embodiments the target cellmay be in vivo or in vitro. In some embodiments the target cell is amammalian cell such as a rodent cell, such as a mouse cell or a ratcell, or a primate cell such as a monkey cell or a human cell. Inpreferred embodiments the target cell is a neuronal cell.

Naturally Occurring Variant

The term “naturally occurring variant” refers to variants of SNHG14transcript downstream of SNORD109B gene or transcripts which originatefrom the same genetic loci as the target nucleic acid, but may differfor example, by virtue of degeneracy of the genetic code causing amultiplicity of codons in the long non-coding RNA. The oligonucleotideof the invention may therefore be designed to target the target nucleicacid and naturally occurring variants thereof.

Modulation of Expression

The term “modulation of expression” as used herein is to be understoodas an overall term for an oligonucleotide's ability to alter the amountof UBE3A protein when compared to the amount of UBE3A beforeadministration of the oligonucleotide. Alternatively modulation ofexpression may be determined by reference to a control experiment wherethe oligonucleotide of the invention is not administered. The modulationeffected by the oligonucleotide is related to it's ability to reduce,remove, prevent, lessen, lower or terminate the suppression of thepaternal UBE3A transcript, e.g. by degradation or removal of thenon-coding SNHG14 transcript downstream of SNORD109B or by blockage orprevention of polymerase activity associated with the SNHG14 transcriptdownstream of SNORD109B. The modulation can also be viewed as theoligonucleotide's ability to restore, increase or enhance expression ofpaternal UBE3A, e.g. by removal or blockage of inhibitory mechanismsaffected by the non-coding SNHG14 transcript downstream of SNORD109B.

High Affinity Modified Nucleosides

A high affinity modified nucleoside is a modified nucleotide which, whenincorporated into the oligonucleotide enhances the affinity of theoligonucleotide for its complementary target, for example as measured bythe melting temperature (T^(m)). A high affinity modified nucleoside ofthe present invention preferably result in an increase in meltingtemperature between +0.5 to +12° C., more preferably between +1.5 to+10° C. and most preferably between +3 to +8° C. per modifiednucleoside. Numerous high affinity modified nucleosides are known in theart and include for example, many 2′ substituted nucleosides as well aslocked nucleic acids (LNA) (see e.g. Freier & Altmann; Nucl. Acid Res.,1997, 25, 4429-4443 and Uhlmann; Curr. Opinion in Drug Development,2000, 3(2), 293-213).

Sugar Modifications

The oligomer of the invention may comprise one or more nucleosides whichhave a modified sugar moiety, i.e. a modification of the sugar moietywhen compared to the ribose sugar moiety found in DNA and RNA.

Numerous nucleosides with modification of the ribose sugar moiety havebeen made, primarily with the aim of improving certain properties ofoligonucleotides, such as affinity and/or nuclease resistance.

Such modifications include those where the ribose ring structure ismodified, e.g. by replacement with a hexose ring (HNA), or a bicyclicring, which typically have a biradicle bridge between the C2 and C4carbons on the ribose ring (LNA), or an unlinked ribose ring whichtypically lacks a bond between the C2 and C3 carbons (e.g. UNA). Othersugar modified nucleosides include, for example, bicyclohexose nucleicacids (WO2011/017521) or tricyclic nucleic acids (WO2013/154798).Modified nucleosides also include nucleosides where the sugar moiety isreplaced with a non-sugar moiety, for example in the case of peptidenucleic acids (PNA), or morpholino nucleic acids.

Sugar modifications also include modifications made via altering thesubstituent groups on the ribose ring to groups other than hydrogen, orthe 2′-OH group naturally found in DNA and RNA nucleosides. Substituentsmay, for example be introduced at the 2′, 3′, 4′ or 5′ positions.Nucleosides with modified sugar moieties also include 2′ modifiednucleosides, such as 2′ substituted nucleosides. Indeed, much focus hasbeen spent on developing 2′ substituted nucleosides, and numerous 2′substituted nucleosides have been found to have beneficial propertieswhen incorporated into oligonucleotides, such as enhanced nucleosideresistance and enhanced affinity.

2′ Modified Nucleosides.

A 2′ sugar modified nucleoside is a nucleoside which has a substituentother than H or —OH at the 2′ position (2′ substituted nucleoside) orcomprises a 2′ linked biradicle, and includes 2′ substituted nucleosidesand LNA (2′-4′ biradicle bridged) nucleosides. For example, the 2′modified sugar may provide enhanced binding affinity and/or increasednuclease resistance to the oligonucleotide. Examples of 2′ substitutedmodified nucleosides are 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA,2′-O-methoxyethyl-RNA (MOE), 2′-amino-DNA, 2′-Fluoro-RNA, and2′-fluoro-ANA (F-ANA). For further examples, please see e.g. Freier &Altmann; Nucl. Acid Res., 1997, 25, 4429-4443 and Uhlmann; Curr. Opinionin Drug Development, 2000, 3(2), 293-213; and Deleavey and Damha,Chemistry and Biology 2012, 19, 937. Below are illustrations of some 2′substituted modified nucleosides.

Locked Nucleic Acid Nucleosides (LNA).

LNA nucleosides are modified nucleosides which comprise a linker group(referred to as a biradicle or a bridge) between C2′ and C4′ of theribose sugar ring of a nucleotide. These nucleosides are also termedbridged nucleic acid or bicyclic nucleic acid (BNA) in the literature.

In some embodiments, the modified nucleoside or the LNA nucleosides ofthe oligomer of the invention has a general structure of the formula Ior II:

wherein W is selected from —O—, —S—, —N(R^(a))—, —C(R^(a)R^(b))—, suchas, in some embodiments —O—;B designates a nucleobase or modified nucleobase moiety;Z designates an internucleoside linkage to an adjacent nucleoside, or a5′-terminal group;Z* designates an internucleoside linkage to an adjacent nucleoside, or a3′-terminal group;X designates a group selected from the list consisting of—C(R^(a)R^(b))—, —C(R^(a))═C(R^(b))—, —C(R^(a))═N—, —O—, —Si(R^(a))₂—,—S—, —SO₂—, —N(R^(a))—, and >C═Z

-   -   In some embodiments, X is selected from the group consisting of:        —O—, —S—, NH—, NR^(a)R^(b), —CH₂—, CR^(a)R^(b), —C(═CH₂)—, and        —C(═CR^(a)R^(b))—    -   In some embodiments, X is —O—        Y designates a group selected from the group consisting of        —C(R^(a)R^(b))—, —C(R^(a))═C(R^(b))—, —C(R^(a))═N—, —O—,        —Si(R^(a))₂—, —S—, —SO₂—, —N(R^(a))—, and >C═Z    -   In some embodiments, Y is selected from the group consisting of:        —CH₂—, —C(R^(a)R^(b))—, —CH₂CH₂—, —C(R^(a)R^(b))—C(R^(a)R^(b))—,        —CH₂CH₂CH₂—, —C(R^(a)R^(b))C(R^(a)R^(b))C(R^(a)R^(b))—,        —C(R^(a))═C(R^(b))—, and —C(R^(a))═N—    -   In some embodiments, Y is selected from the group consisting of:        —CH₂—, —CHR^(a)—, —CHCH₃—, CR^(a)R^(b)—        or —X—Y— together designate a bivalent linker group (also        referred to as a radical) together designate a bivalent linker        group consisting of 1, 2, 3 or 4 groups/atoms selected from the        group consisting of —C(R^(a)R^(b))—, —C(R^(a))═C(R^(b))—,        —C(R^(a))═N—, —O—, —Si(R^(a))₂—, —S—, —SO₂—, —N(R^(a))—, and        >C═Z,    -   In some embodiments, —X—Y— designates a biradicle selected from        the groups consisting of: —X—CH₂—, —X—CR^(a)R^(b)—, —X—CHR^(a)—,        —X—C(HCH₃)—, —O—Y—, —O—CH₂—, —S—CH₂—, —NH—CH₂—, —O—CHCH₃—,        —CH₂—O—CH₂, —O—CH(CH₃CH₃)—, —O—CH₂—CH₂—, OCH₂—CH₂—CH₂—,        —O—CH₂OCH₂—, —O—NCH₂—, —C(═CH₂)—CH₂—, —NR^(a)—CH₂—, N—O—CH₂,        —S—CR^(a)R^(b)— and —S—CHR^(a)—.    -   In some embodiments —X—Y— designates —O—CH₂— or —O—CH(CH₃)—.        wherein Z is selected from —O—, —S—, and —N(R^(a))—,        and R^(a) and, when present R^(b), each is independently        selected from hydrogen, optionally substituted C₁₋₆-alkyl,        optionally substituted C₂₋₆-alkenyl, optionally substituted        C₂₋₆-alkynyl, hydroxy, optionally substituted C₁₋₆-alkoxy,        C₂₋₆-alkoxyalkyl, C₂₋₆-alkenyloxy, carboxy, C₁₋₆-alkoxycarbonyl,        C₁₋₆-alkylcarbonyl, formyl, aryl, aryloxy-carbonyl, aryloxy,        arylcarbonyl, heteroaryl, heteroaryloxy-carbonyl, heteroaryloxy,        heteroarylcarbonyl, amino, mono- and di(C₁₋₆-alkyl)amino,        carbamoyl, mono- and di(C₁₋₆-alkyl)-amino-carbonyl,        amino-C₁₋₆-alkyl-aminocarbonyl, mono- and        di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl,        C₁₋₆-alkyl-carbonylamino, carbamido, C₁₋₆-alkanoyloxy, sulphono,        C₁₋₆-alkylsulphonyloxy, nitro, azido, sulphanyl, C₁₋₆-alkylthio,        halogen, where aryl and heteroaryl may be optionally substituted        and where two geminal substituents R^(a) and R^(b) together may        designate optionally substituted methylene (═CH₂), wherein for        all chiral centers, asymmetric groups may be found in either R        or S orientation.        wherein R¹, R², R³, R⁵ and R^(5*) are independently selected        from the group consisting of: hydrogen, optionally substituted        C₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl, optionally        substituted C₂₋₆-alkynyl, hydroxy, C₁₋₆-alkoxy,        C₂₋₆-alkoxyalkyl, C₂₋₆-alkenyloxy, carboxy, C₁₋₆-alkoxycarbonyl,        C₁₋₆-alkylcarbonyl, formyl, aryl, aryloxy-carbonyl, aryloxy,        arylcarbonyl, heteroaryl, heteroaryloxy-carbonyl, heteroaryloxy,        heteroarylcarbonyl, amino, mono- and di(C₁₋₆-alkyl)amino,        carbamoyl, mono- and di(C₁₋₆-alkyl)-amino-carbonyl,        amino-C₁₋₆-alkyl-aminocarbonyl, mono- and        di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl,        C₁₋₆-alkyl-carbonylamino, carbamido, C₁₋₆-alkanoyloxy, sulphono,        C₁₋₆-alkylsulphonyloxy, nitro, azido, sulphanyl, C₁₋₆-alkylthio,        halogen, where aryl and heteroaryl may be optionally        substituted, and where two geminal substituents together may        designate oxo, thioxo, imino, or optionally substituted        methylene.    -   In some embodiments R¹, R², R³, R⁵ and R^(5*) are independently        selected from C₁₋₆ alkyl, such as methyl, and hydrogen.    -   In some embodiments R¹, R², R³, R⁵ and R^(5*) are all hydrogen.    -   In some embodiments R¹, R², R³, are all hydrogen, and either R⁵        and R^(5*) is also hydrogen and the other of R⁵ and R^(5*) is        other than hydrogen, such as C₁₋₆ alkyl such as methyl.    -   In some embodiments, R^(a) is either hydrogen or methyl. In some        embodiments, when present, R^(b) is either hydrogen or methyl.    -   In some embodiments, one or both of R^(a) and R^(b) is hydrogen    -   In some embodiments, one of R^(a) and R^(b) is hydrogen and the        other is other than hydrogen    -   In some embodiments, one of R^(a) and R^(b) is methyl and the        other is hydrogen    -   In some embodiments, both of R^(a) and R^(b) are methyl.

In some embodiments, the biradicle —X—Y— is —O—CH₂—, W is O, and all ofR¹, R², R³, R⁵ and R^(5*) are all hydrogen. Such LNA nucleosides aredisclosed in WO99/014226, WO00/66604, WO98/039352 and WO2004/046160which are all hereby incorporated by reference, and include what arecommonly known as beta-D-oxy LNA and alpha-L-oxy LNA nucleosides.

In some embodiments, the biradicle —X—Y— is —S—CH₂—, W is O, and all ofR¹, R², R³, R⁵ and R^(5*) are all hydrogen. Such thio LNA nucleosidesare disclosed in WO99/014226 and WO2004/046160 which are herebyincorporated by reference.

In some embodiments, the biradicle —X—Y— is —NH—CH₂—, W is O, and all ofR¹, R², R³, R⁵ and R^(5*) are all hydrogen. Such amino LNA nucleosidesare disclosed in WO99/014226 and WO2004/046160 which are herebyincorporated by reference.

In some embodiments, the biradicle —X—Y— is —O—CH₂—CH₂— or—O—CH₂—CH₂—CH₂—, W is O, and all of R¹, R², R³, R⁵ and R^(5*) are allhydrogen. Such LNA nucleosides are disclosed in WO00/047599 and Moritaet al, Bioorganic & Med. Chem. Lett. 12 73-76, which are herebyincorporated by reference, and include what are commonly known as2′-O-4′C-ethylene bridged nucleic acids (ENA).

In some embodiments, the biradicle —X—Y— is —O—CH₂—, W is O, and all ofR¹, R², R³, and one of R⁵ and R^(5*) are hydrogen, and the other of R⁵and R^(5*) is other than hydrogen such as C₁₋₆ alkyl, such as methyl.Such 5′ substituted LNA nucleosides are disclosed in WO2007/134181 whichis hereby incorporated by reference.

In some embodiments, the biradicle —X—Y— is —O—CR^(a)R^(b)—, wherein oneor both of R^(a) and R^(b) are other than hydrogen, such as methyl, W isO, and all of R¹, R², R³, and one of R⁵ and R^(5*) are hydrogen, and theother of R⁵ and R^(5*) is other than hydrogen such as C₁₋₆ alkyl, suchas methyl. Such bis modified LNA nucleosides are disclosed inWO2010/077578 which is hereby incorporated by reference.

In some embodiments, the biradicle —X—Y— designate the bivalent linkergroup —O—CH(CH₂OCH₃)— (2′ O-methoxyethyl bicyclic nucleic acid—Seth atal., 2010, J. Org. Chem. Vol 75(5) pp. 1569-81). In some embodiments,the biradicle —X—Y— designate the bivalent linker group—O—CH(CH₂CH₃)-(2′O-ethyl bicyclic nucleic acid—Seth at al., 2010, J.Org. Chem. Vol 75(5) pp. 1569-81). In some embodiments, the biradicle—X—Y— is —O—CHR^(a)—, W is O, and all of R¹, R², R³, R⁵ and R^(5*) areall hydrogen. Such 6′ substituted LNA nucleosides are disclosed inWO10036698 and WO07090071 which are both hereby incorporated byreference.

In some embodiments, the biradicle —X—Y— is —O—CH(CH₂OCH₃)—, W is O, andall of R¹, R², R³, R⁵ and R^(5*) are all hydrogen. Such LNA nucleosidesare also known as cyclic MOEs in the art (cMOE) and are disclosed inWO07090071.

In some embodiments, the biradicle —X—Y— designate the bivalent linkergroup —O—CH(CH₃)—.—in either the R- or S-configuration. In someembodiments, the biradicle —X—Y— together designate the bivalent linkergroup —O—CH₂—O—CH₂— (Seth at al., 2010, J. Org. Chem). In someembodiments, the biradicle —X—Y— is —O—CH(CH₃)—, W is O, and all of R¹,R², R³, R⁵ and R^(5*) are all hydrogen. Such 6′ methyl LNA nucleosidesare also known as cET nucleosides in the art, and may be either (S)cETor (R)cET stereoisomers, as disclosed in WO07090071 (beta-D) andWO2010/036698 (alpha-L) which are both hereby incorporated byreference).

In some embodiments, the biradicle —X—Y— is —O—CR^(a)R^(b)—, wherein inneither R^(a) or R^(b) is hydrogen, W is O, and all of R¹, R², R³, R⁵and R^(5*) are all hydrogen. In some embodiments, R^(a) and R^(b) areboth methyl. Such 6′ di-substituted LNA nucleosides are disclosed in WO2009006478 which is hereby incorporated by reference.

In some embodiments, the biradicle —X—Y— is —S—CHR^(a)—, W is O, and allof R¹, R², R³, R⁵ and R^(5*) are all hydrogen. Such 6′ substituted thioLNA nucleosides are disclosed in WO11156202 which is hereby incorporatedby reference. In some 6′ substituted thio LNA embodiments R^(a) ismethyl.

In some embodiments, the biradicle —X—Y— is —C(═CH₂)—C(R^(a)R^(b))—,such as —C(═CH₂)—CH₂—, or —C(═CH₂)—CH(CH₃)—W is O, and all of R¹, R²,R³, R⁵ and R^(5*) are all hydrogen. Such vinyl carbo LNA nucleosides aredisclosed in WO08154401 and WO09067647 which are both herebyincorporated by reference.

In some embodiments the biradicle —X—Y— is —N(—OR^(a))—, W is O, and allof R¹, R², R³, R⁵ and R^(5*) are all hydrogen. In some embodiments R^(a)is C₁₋₆ alkyl such as methyl. Such LNA nucleosides are also known as Nsubstituted LNAs and are disclosed in WO2008/150729 which is herebyincorporated by reference. In some embodiments, the biradicle —X—Y—together designate the bivalent linker group —O—NR^(a)—CH₃— (Seth atal., 2010, J. Org. Chem). In some embodiments the biradicle —X—Y— is—N(R^(a))—, W is O, and all of R¹, R², R³, R⁵ and R^(5*) are allhydrogen. In some embodiments R^(a) is C₁₋₆ alkyl such as methyl.

In some embodiments, one or both of R⁵ and R^(5*) is hydrogen and, whensubstituted the other of R⁵ and R^(5*) is C₁₋₆ alkyl such as methyl. Insuch an embodiment, R¹, R², R³, may all be hydrogen, and the biradicle—X—Y— may be selected from —O—CH2- or —O—C(HCR^(a))—, such as—O—C(HCH3)-.

In some embodiments, the biradicle is —CR^(a)R^(b)—O—CR^(a)R^(b)—, suchas CH₂—O—CH₂—, W is O and all of R¹, R², R³, R⁵ and R^(5*) are allhydrogen. In some embodiments R^(a) is C₁₋₆ alkyl such as methyl. SuchLNA nucleosides are also known as conformationally restrictednucleotides (CRNs) and are disclosed in WO2013036868 which is herebyincorporated by reference.

In some embodiments, the biradicle is —O—CR^(a)R^(b)—O—CR^(a)R^(b)—,such as O—CH₂—O—CH₂—, W is O and all of R¹, R², R³, R⁵ and R^(5*) areall hydrogen. In some embodiments R^(a) is C₁₋₆ alkyl such as methyl.Such LNA nucleosides are also known as COC nucleotides and are disclosedin Mitsuoka et al., Nucleic Acids Research 2009 37(4), 1225-1238, whichis hereby incorporated by reference.

It will be recognized than, unless specified, the LNA nucleosides may bein the beta-D or alpha-L stereoisoform.

Certain examples of LNA nucleosides are presented in Scheme 1.

As illustrated in the examples, in preferred embodiments of theinvention the LNA nucleosides in the oligonucleotides are beta-D-oxy-LNAnucleosides.

Nuclease Mediated Degradation

Nuclease mediated degradation refers to an oligonucleotide capable ofmediating degradation of a complementary nucleotide sequence whenforming a duplex with such a sequence.

In some embodiments, the oligonucleotide may function via nucleasemediated degradation of the target nucleic acid, where theoligonucleotides of the invention are capable of recruiting a nuclease,particularly and endonuclease, preferably endoribonuclease (RNase), suchas RNase H. Examples of oligonucleotide designs which operate vianuclease mediated mechanisms are oligonucleotides which typicallycomprise a region of at least 5 or 6 DNA nucleosides and are flanked onone side or both sides by affinity enhancing nucleosides, for examplegapmers, headmers and tailmers.

RNase H Activity and Recruitment

The RNase H activity of an antisense oligonucleotide refers to itsability to recruit RNase H when in a duplex with a complementary RNAmolecule. WO01/23613 provides in vitro methods for determining RNaseHactivity, which may be used to determine the ability to recruit RNaseH.Typically an oligonucleotide is deemed capable of recruiting RNase H ifit, when provided with a complementary target nucleic acid sequence, hasan initial rate, as measured in pmol/l/min, of at least 10% or more than20% of the of the initial rate determined when using a oligonucleotidehaving the same base sequence as the modified oligonucleotide beingtested, but containing only DNA monomers, with phosphorothioate linkagesbetween all monomers in the oligonucleotide, and using the methodologyprovided by Example 91-95 of WO01/23613 (hereby incorporated byreference).

Gapmer

The term gapmer as used herein refers to an antisense oligonucleotidewhich comprises a region of RNase H recruiting oligonucleotides (gap)which is flanked 5′ and 3′ by one or more affinity enhancing modifiednucleosides (flanks). Various gapmer designs are described herein.Headmers and tailmers are oligonucleotides capable of recruiting RNase Hwhere one of the flanks is missing, i.e. only one of the ends of theoligonucleotide comprises affinity enhancing modified nucleosides. Forheadmers the 3′ flank is missing (i.e. the 5′ flanc comprise affinityenhancing modified nucleosides) and for tailmers the 5′ flank is missing(i.e. the 3′ flank comprises affinity enhancing modified nucleosides).

LNA Gapmer

The term LNA gapmer is a gapmer oligonucleotide wherein at least one ofthe affinity enhancing modified nucleosides is an LNA nucleoside.

Mixed Wing Gapmer

The term mixed wing gapmer refers to a LNA gapmer wherein the flankregions comprise at least one LNA nucleoside and at least one non-LNAmodified nucleoside, such as at least one 2′ substituted modifiednucleoside, such as, for example, 2′-O-alkyl-RNA, 2′-O-methyl-RNA,2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA (MOE), 2′-amino-DNA, 2′-Fluoro-RNA,and 2′-F-ANA nucleoside(s). In some embodiments the mixed wing gapmerhas one flank which comprises LNA nucleosides (e.g. 5′ or 3′) and theother flank (3′ or 5′ respectfully) comprises 2′ substituted modifiednucleoside(s).

Conjugate

The term conjugate as used herein refers to an oligonucleotide which iscovalently linked to a non-nucleotide moiety (conjugate moiety or regionC or third region).

Conjugation of the oligonucleotide of the invention to one or morenon-nucleotide moieties may improve the pharmacology of theoligonucleotide, e.g. by affecting the activity, cellular distribution,cellular uptake or stability of the oligonucleotide. In some embodimentsthe conjugate moiety modify or enhance the pharmacokinetic properties ofthe oligonucleotide by improving cellular distribution, bioavailability,metabolism, excretion, permeability, and/or cellular uptake of theoligonucleotide. In particular the conjugate may target theoligonucleotide to a specific organ, tissue or cell type and therebyenhance the effectiveness of the oligonucleotide in that organ, tissueor cell type. A the same time the conjugate may serve to reduce activityof the oligonucleotide in non-target cell types, tissues or organs, e.g.off target activity or activity in non-target cell types, tissues ororgans. WO 93/07883 and WO 2013/033230 provides suitable conjugatemoieties, which are hereby incorporated by reference. WO 2012/143379provides a method of delivering a drug across the blood-brain-barrier byconjugation to an antibody fragment with affinity to the transferrinreceptor, which are hereby incorporated by reference.

Oligonucleotide conjugates and their synthesis has also been reported incomprehensive reviews by Manoharan in Antisense Drug Technology,Principles, Strategies, and Applications, S. T. Crooke, ed., Ch. 16,Marcel Dekker, Inc., 2001 and Manoharan, Antisense and Nucleic Acid DrugDevelopment, 2002, 12, 103, each of which is incorporated herein byreference in its entirety.

In an embodiment, the non-nucleotide moiety (conjugate moiety) isselected from the group consisting of carbohydrates, cell surfacereceptor ligands, drug substances, hormones, lipophilic substances,polymers, proteins, peptides, toxins (e.g. bacterial toxins), vitamins,viral proteins (e.g. capsids) or combinations thereof. In someembodiments the non-nucleotide moiety an antibody or antibody fragment,such as an antibody or antibody fragment that facilitates deliveryacross the blood-brain-barrier, in particular an antibody or antibodyfragment targeting the transferrin receptor.

Linkers

A linkage or linker is a connection between two atoms that links onechemical group or segment of interest to another chemical group orsegment of interest via one or more covalent bonds. Conjugate moietiescan be attached to the oligonucleotide directly or through a linkingmoiety (e.g. linker or tether). Linkers serve to covalently connect athird region, e.g. a conjugate moiety (Region C), to a first region,e.g. an oligonucleotide (region A).

In some embodiments of the invention the conjugate or oligonucleotideconjugate of the invention may optionally, comprise a linker region(second region or region B and/or region Y) which is positioned betweenthe oligonucleotide (region A or first region) and the conjugate moiety(region C or third region).

Region B refers to biocleavable linkers comprising or consisting of aphysiologically labile bond that is cleavable under conditions normallyencountered or analogous to those encountered within a mammalian body.Conditions under which physiologically labile linkers undergo chemicaltransformation (e.g., cleavage) include chemical conditions such as pH,temperature, oxidative or reductive conditions or agents, and saltconcentration found in or analogous to those encountered in mammaliancells. Mammalian intracellular conditions also include the presence ofenzymatic activity normally present in a mammalian cell such as fromproteolytic enzymes or hydrolytic enzymes or nucleases. In oneembodiment the biocleavable linker is susceptible to S1 nucleasecleavage. In a preferred embodiment the nuclease susceptible linkercomprises between 1 and 10 nucleosides, such as 1, 2, 3, 4, 5, 6, 7, 8,9 or 10 nucleosides, more preferably between 2 and 6 nucleosides andmost preferably between 2 and 4 linked nucleosides comprising at leasttwo consecutive phosphodiester linkages, such as at least 3 or 4 or 5consecutive phosphodiester linkages. Preferably the nucleosides are DNAor RNA. Phosphodiester containing biocleavable linkers are described inmore detail in WO 2014/076195 (hereby incorporated by reference).

Region Y refers to linkers that are not necessarily biocleavable butprimarily serve to covalently connect a conjugate moiety (region C orthird region), to an oligonucleotide (region A or first region). Theregion Y linkers may comprise a chain structure or an oligomer ofrepeating units such as ethylene glycol, amino acid units or amino alkylgroups The oligonucleotide conjugates of the present invention can beconstructed of the following regional elements A-C, A-B-C, A-B-Y-C,A-Y-B-C or A-Y-C. In some embodiments the linker (region Y) is an aminoalkyl, such as a C2-C36 amino alkyl group, including, for example C6 toC12 amino alkyl groups. In a preferred embodiment the linker (region Y)is a C6 amino alkyl group.

Control

By the term “control” when used in relation to measurements of theeffect of an oligonucleotide it is generally understood that the controlis an untreated individual or target cell or a individual or target celltreated with a non-targeting oligonucleotide (mock). It may however alsobe an individual treated with the standard of care.

Treatment

The term ‘treatment’ as used herein refers to both treatment of anexisting disease (e.g. a disease or disorder as herein referred to), orprevention of a disease, i.e. prophylaxis. It will therefore berecognized that treatment as referred to herein may, in someembodiments, be prophylactic.

DETAILED DESCRIPTION OF THE INVENTION

The Target

An aspect of the invention is to modulate the level of pig, primate orhuman UBE3A protein expression, in particular to increase the expressionof paternal UBE3A expression in neuronal cells, in particular in humanneuronal cells. The human UBE3A protein exists in several isoforms whichare listed under Uniprot nr. Q05086. Several mutations in the maternalUBE3A gene can results in Angelman syndrome.

The target nucleic acid for the oligonucleotides of the invention isRNA, in particular a long non-coding RNA. The long non-coding RNA whichis targeted by the oligonucleotides of the present invention is humanSNHG14 (also known as UBE3A-ATS with Ensembl entry numberENSG00000224078, version GRCh38.p2). In particular the target nucleicacid is the region downstream of SNORD109B corresponding to position25278410 to 25419462 on chromosome 15 (SEQ ID NO: 1). In Rhesus monkey(Macaca mulatta) the UBE3A suppressor is defined as region downstream ofSNORD109A corresponding to position 4222848 to U.S. Pat. No. 4,373,084(forward strand) on chromosome 7 using the Ensembl assembly MMUL 1.0(SEQ ID NO: 2).

In some embodiments, the target nucleic acid is SEQ ID NO: 1, ornaturally occurring variants thereof.

In certain embodiments the target nucleic acid correspond to regionswhich are conserved between human (SEQ ID NO: 1) and Rhesus monkey (SEQID NO: 2). In certain embodiments target nucleic acid correspond toregions which are conserved between human (SEQ ID NO:1), Rhesus monkey(SEQ ID NO: 2) and mouse (SEQ ID NO: 3).

In certain embodiments the target nucleic acid is the region that isantisense to the UBE3A pre-mRNA, this region corresponds to position55319 to 141053 of SEQ ID NO: 1.

In certain embodiments the target nucleic acid is the region that isdownstream of SNORD109B and upstream of the region that is antisense tothe UBE3A pre-mRNA, this region corresponds to position 1 to 55319 ofSEQ ID NO: 1.

In some embodiments, the target nucleic acid is present in a cell, suchas a mammalian cell in particular a human cell in vitro or in vivo (thetarget cell). In certain embodiments the target cell is a neuron,preferably a human neuronal cell.

The target sequence may be a sub-sequence of the target nucleic acid. Insome embodiments the oligonucleotide targets sub-sequence selected fromthe group consisting of the antisense region of exon 9, exon10, exon13,exon14, intron 14, exon 15, intron15 and exon 16 of UBE3A. In someembodiments the oligonucleotide or contiguous nucleotide sequencehybridize or is complementary to a single stranded nucleic acid moleculeselected from the group consisting of positions: 55319-76274,77483-77573, 92157-93403 and 97056-97354 of SEQ ID NO: 1. In someembodiments the oligonucleotide or contiguous nucleotide sequencehybridize or is complementary to a single stranded nucleic acid moleculeselected from the group consisting of positions: 60821-60849,77567-77583, 92323-92339 and 97156-97172 of SEQ ID NO: 1.

In some embodiments the target nucleic acid is a region corresponding topositions 9200-9250 of SEQ ID NO: 1.

In some embodiments the target nucleic acid is a region corresponding topositions 11505-11555 of SEQ ID NO: 1.

In some embodiments the target nucleic acid is a region corresponding topositions 15100-15150 of SEQ ID NO: 1.

In some embodiments the target nucleic acid is a region corresponding topositions 30590-30740 of SEQ ID NO: 1.

In some embodiments the target nucleic acid is a region corresponding topositions 46380-46430 of SEQ ID NO: 1.

The Oligonucleotides of the Invention

The invention relates to oligonucleotides capable of modulatingexpression of paternal UBE3A, in particular induction or up-regulationof paternally expressed UBE3A in neuronal cells. The modulation isachieved by hybridizing to a target nucleic acid located on the longnon-coding RNA SNHG14 transcript downstream of SNORD109B. In certainembodiments the oligonucleotide of the invention hybridizes to asub-sequence of the target nucleic acid of SEQ ID NO: 1 with a ΔG° below−10 kcal, such as with a ΔG° between −10 to −60 kcal, such as −12 to−40, such as from −15 to −30 kcal or −16 to −27 kcal such as −18 to −25kcal.

The oligonucleotide of the invention is an antisense oligonucleotidewhich targets the pig, rhesus monkey and/or human SNHG14 transcriptdownstream of SNORD109B.

In some embodiments the antisense oligonucleotide of the invention iscapable of modulating the expression of the target by removing,interfering with or decreasing the suppressor of the target. Preferably,the oligonucleotides of the invention induce UBE3A expression in a cell,in particular paternal UBE3A expression in a neuron, by degradation orremoval of the SNHG14 transcript downstream of SNORD109B. In someembodiments the oligonucleotides of the invention are capable ofincreasing the expression of UBE3A by least 20% compared to theexpression level of UBE3A in a neuronal cell treated with saline or anon-targeting oligonucleotide, more preferably by at least 30%, 35%,40%, 45%, 50%, 55%, 60%, 80%, 100%, 120%, 150%, 160%, 170%, 180%, 190%,200%, 210%, 220%, 230%, 240% or 250% compared to the expression level ofUBE3A in a neuronal cell treated with saline or a non-targetingoligonucleotide. In additional embodiments the oligonucleotides of theinvention are capable of decreasing the level of the SNHG14 transcriptdownstream of SNORD109B (in particular the part of the transcript thatis antisense to the UBE3A pre-mRNA region) by at least 20% compared tothe level of the SNHG14 transcript downstream of SNORD109B in a neuronalcell treated with saline or a non-targeting oligonucleotide, morepreferably by at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% comparedto the level of the SNHG14 transcript downstream of SNORD109B in aneuronal cell treated with saline or a non-targeting oligonucleotide,without reducing SNORD115 levels by more than 0%, 1%, 2%, 3%, 4%, 5%,6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25% or 30% compared to thelevel of SNORD115 in a cell treated with saline or a non-targetingoligonucleotide. SNRPN and SNORD116 transcripts are located upstreamfrom the SNORD115 transcript consequently if the SNORD115 transcript isnot reduced by the oligonucleotide it is highly likely that the SNRPNand SNORD116 transcripts are also not reduced. In a further embodimentSNRPN and SNORD116 transcripts levels are not reduced by more than 0%,1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25% or30% compared to the level of SNRPN and SNORD116 in a cell treated withsaline or a non-targeting oligonucleotide.

The target modulation is triggered by the hybridization between acontiguous nucleotide sequence of the oligonucleotide and the targetnucleic acid. In some embodiments the oligonucleotide of the inventioncomprises mismatches between the oligonucleotide and the target nucleicacid. Despite mismatches hybridization to the target nucleic acid maystill be sufficient to show a desired modulation of UBE3A expression.Reduced binding affinity resulting from mismatches may advantageously becompensated by increased number of nucleotides in the oligonucleotideand/or an increased number of modified nucleosides capable of increasingthe binding affinity to the target, such as 2′ modified nucleosides,including LNA, present within the oligonucleotide sequence.

An aspect of the present invention relates to an antisenseoligonucleotide which comprises a contiguous nucleotide sequence of 10to 30 nucleotides in length with at least 90%, such as 95%, such as 98%such as 100% complementarity to position 25278410 to 25419462 on humanchromosome 15.

In some embodiments, the oligonucleotide comprises a contiguous sequencewhich is at least 90% complementary, such as at least 91%, such as atleast 92%, such as at least 93%, such as at least 94%, such as at least95%, such as at least 96%, such as at least 97%, such as at least 98%,or 100% complementary with a region of the target nucleic acid shown asSEQ ID NO: 1, 2 or 3.

In a preferred embodiment the oligonucleotide of the invention, orcontiguous nucleotide sequence thereof is fully complementary (100%complementary) to a region of the target nucleic acid shown as SEQ IDNO: 1, or in some embodiments may comprise one or two mismatches betweenthe oligonucleotide and the target nucleic acid.

In some embodiments the oligonucleotide sequence is 100% complementaryto a corresponding target nucleic acid region present in SEQ ID NO: 1and SEQ ID NO: 2. In some embodiments the oligonucleotide sequence is100% complementary to a corresponding target nucleic acid region presentSEQ ID NO: 1, 2 and 3.

In some embodiments, the oligonucleotide comprises a contiguousnucleotide sequence of 10 to 30 nucleotides in length with at least 90%complementary, such as 100% complementarity, to a corresponding targetnucleic acid region present in SEQ ID NO: 1, wherein the target nucleicacid region is selected from the group consisting of region A1 to A3649in table 1

TABLE 1 Regions of SEQ ID NO 1 which may be targeted usingoligonucleotide of the invention Position in SEQ ID NO 1 Reg. A from toLength 1 10 75 66 2 77 91 15 3 93 108 16 4 168 213 46 5 217 282 66 6 284299 16 7 301 328 28 8 330 344 15 9 361 400 40 10 415 447 33 11 449 47022 12 472 487 16 13 489 521 33 14 523 540 18 15 551 570 20 16 590 638 4917 652 670 19 18 672 733 62 19 735 756 22 20 758 773 16 21 781 829 49 22831 870 40 23 882 903 22 24 918 949 32 25 961 990 30 26 1007 1021 15 271019 1050 32 28 1052 1090 39 29 1092 1139 48 30 1147 1179 33 31 11751212 38 32 1220 1242 23 33 1245 1259 15 34 1265 1278 14 35 1285 1323 3936 1317 1330 14 37 1337 1355 19 38 1357 1403 47 39 1405 1421 17 40 14231481 59 41 1486 1515 30 42 1521 1581 61 43 1611 1633 23 44 1631 1644 1445 1635 1663 29 46 1669 1684 16 47 1685 1709 25 48 1711 1724 14 49 17261746 21 50 1754 1808 55 51 1819 1860 42 52 1862 1878 17 53 1896 1910 1554 1923 1944 22 55 1946 1987 42 56 1985 2051 67 57 2053 2082 30 58 20882104 17 59 2106 2125 20 60 2132 2207 76 61 2209 2234 26 62 2247 2261 1563 2263 2286 24 64 2290 2306 17 65 2308 2329 22 66 2347 2391 45 67 23982431 34 68 2447 2468 22 69 2470 2555 86 70 2565 2579 15 71 2579 2592 1472 2589 2605 17 73 2594 2657 64 74 2672 2687 16 75 2692 2705 14 76 27032721 19 77 2770 2824 55 78 2826 2841 16 79 2838 2851 14 80 2843 2889 4781 2896 2930 35 82 2930 2967 38 83 2965 2988 24 84 2984 3028 45 85 30243080 57 86 3081 3135 55 87 3140 3176 37 88 3168 3189 22 89 3197 3222 2690 3212 3226 15 91 3221 3248 28 92 3243 3256 14 93 3250 3264 15 94 32663292 27 95 3326 3343 18 96 3345 3391 47 97 3400 3422 23 98 3424 3441 1899 3434 3447 14 100 3443 3503 61 101 3495 3508 14 102 3505 3558 54 1033589 3609 21 104 3611 3641 31 105 3662 3696 35 106 3698 3719 22 107 37233790 68 108 3810 3854 45 109 3858 3873 16 110 3902 3968 67 111 3971 400939 112 4005 4018 14 113 4011 4030 20 114 4032 4077 46 115 4082 4114 33116 4123 4140 18 117 4150 4164 15 118 4166 4183 18 119 4185 4243 59 1204248 4268 21 121 4284 4313 30 122 4317 4348 32 123 4364 4471 108 1244473 4491 19 125 4494 4519 26 126 4521 4535 15 127 4545 4560 16 128 45674606 40 129 4616 4714 99 130 4725 4755 31 131 4757 4786 30 132 4788 485265 133 4856 4910 55 134 4912 4935 24 135 4937 4970 34 136 4972 5010 39137 5058 5078 21 138 5080 5116 37 139 5110 5124 15 140 5135 5166 32 1415168 5201 34 142 5203 5247 45 143 5261 5276 16 144 5278 5293 16 145 53145330 17 146 5332 5382 51 147 5398 5414 17 148 5427 5456 30 149 5458 547114 150 5487 5500 14 151 5506 5545 40 152 5561 5577 17 153 5580 5617 38154 5607 5620 14 155 5619 5642 24 156 5644 5683 40 157 5685 5698 14 1585713 5759 47 159 5756 5769 14 160 5784 5803 20 161 5801 5865 65 162 58735905 33 163 5907 5937 31 164 5939 5985 47 165 5987 6017 31 166 6016 603924 167 6028 6092 65 168 6102 6127 26 169 6127 6152 26 170 6151 6171 21171 6178 6206 29 172 6217 6234 18 173 6224 6270 47 174 6272 6289 18 1756291 6310 20 176 6312 6357 46 177 6367 6389 23 178 6396 6422 27 179 64406454 15 180 6456 6482 27 181 6484 6513 30 182 6505 6519 15 183 6518 655336 184 6552 6565 14 185 6557 6590 34 186 6596 6628 33 187 6640 6675 36188 6686 6711 26 189 6714 6746 33 190 6781 6818 38 191 6832 6885 54 1926889 6912 24 193 6920 6938 19 194 6940 6960 21 195 6954 6976 23 196 69987033 36 197 7035 7061 27 198 7071 7143 73 199 7159 7214 56 200 7253 726614 201 7268 7281 14 202 7283 7328 46 203 7329 7343 15 204 7338 7355 18205 7345 7374 30 206 7374 7387 14 207 7383 7396 14 208 7389 7405 17 2097399 7413 15 210 7420 7437 18 211 7427 7448 22 212 7450 7503 54 213 74957565 71 214 7561 7616 56 215 7618 7703 86 216 7717 7772 56 217 7776 783863 218 7852 7869 18 219 7882 7910 29 220 7919 7942 24 221 7944 7957 14222 7959 7977 19 223 7979 7996 18 224 7998 8014 17 225 8030 8046 17 2268059 8092 34 227 8100 8113 14 228 8115 8141 27 229 8143 8175 33 230 81798192 14 231 8187 8208 22 232 8205 8219 15 233 8210 8229 20 234 8231 825222 235 8254 8298 45 236 8302 8316 15 237 8306 8329 24 238 8331 8357 27239 8400 8443 44 240 8443 8456 14 241 8445 8460 16 242 8472 8505 34 2438494 8507 14 244 8554 8569 16 245 8571 8653 83 246 8659 8673 15 247 86758694 20 248 8696 8713 18 249 8736 8844 109 250 8847 8909 63 251 89158959 45 252 8961 8975 15 253 8993 9009 17 254 9024 9048 25 255 9050 906314 256 9089 9120 32 257 9127 9166 40 258 9191 9249 59 259 9257 9285 29260 9288 9302 15 261 9331 9397 67 262 9399 9438 40 263 9437 9455 19 2649483 9505 23 265 9507 9526 20 266 9583 9598 16 267 9600 9613 14 268 96289641 14 269 9653 9674 22 270 9676 9690 15 271 9745 9758 14 272 9752 978029 273 9796 9809 14 274 9811 9825 15 275 9832 9853 22 276 9877 9899 23277 9901 9932 32 278 10000 10016 17 279 10029 10049 21 280 10051 1007121 281 10089 10120 32 282 10111 10127 17 283 10122 10203 82 284 1021110237 27 285 10239 10256 18 286 10258 10285 28 287 10287 10304 18 28810306 10350 45 289 10352 10375 24 290 10381 10402 22 291 10412 10470 59292 10474 10488 15 293 10508 10557 50 294 10565 10630 66 295 10632 1067443 296 10698 10711 14 297 10701 10714 14 298 10704 10718 15 299 1072010740 21 300 10742 10785 44 301 10786 10809 24 302 10811 10829 19 30310832 10867 36 304 10869 10930 62 305 10932 10950 19 306 10959 10996 38307 10998 11028 31 308 11037 11077 41 309 11079 11105 27 310 11115 1113218 311 11134 11154 21 312 11156 11196 41 313 11206 11239 34 314 1124111255 15 315 11266 11287 22 316 11299 11329 31 317 11331 11352 22 31811358 11403 46 319 11405 11432 28 320 11434 11480 47 321 11482 11535 54322 11539 11573 35 323 11584 11732 149 324 11731 11763 33 325 1176511782 18 326 11784 11813 30 327 11815 11829 15 328 11831 11852 22 32911854 11871 18 330 11866 11895 30 331 11930 11943 14 332 11975 12007 33333 11996 12012 17 334 12017 12040 24 335 12050 12083 34 336 12088 1211124 337 12133 12151 19 338 12161 12174 14 339 12179 12225 47 340 1223812256 19 341 12265 12278 14 342 12296 12360 65 343 12362 12381 20 34412384 12399 16 345 12400 12475 76 346 12487 12502 16 347 12504 12531 28348 12533 12562 30 349 12564 12602 39 350 12627 12646 20 351 12655 1267925 352 12681 12698 18 353 12700 12812 113 354 12828 12876 49 355 1287712913 37 356 12932 12945 14 357 12936 12967 32 358 12988 13002 15 35912996 13009 14 360 13018 13035 18 361 13031 13049 19 362 13056 13093 38363 13096 13126 31 364 13128 13142 15 365 13144 13193 50 366 13201 1322121 367 13223 13280 58 368 13282 13298 17 369 13300 13315 16 370 1330713320 14 371 13315 13331 17 372 13351 13411 61 373 13422 13437 16 37413439 13456 18 375 13461 13483 23 376 13485 13541 57 377 13543 13560 18378 13574 13606 33 379 13618 13646 29 380 13778 13801 24 381 13994 1400916 382 14508 14521 14 383 15049 15067 19 384 15069 15090 22 385 1510215139 38 386 15142 15180 39 387 15182 15205 24 388 15238 15252 15 38915254 15277 24 390 15292 15320 29 391 15322 15348 27 392 15343 15358 16393 15362 15387 26 394 15399 15414 16 395 15416 15445 30 396 15459 1552870 397 15537 15592 56 398 15610 15638 29 399 15640 15653 14 400 1565515717 63 401 15719 15738 20 402 15757 15778 22 403 15783 15801 19 40415818 15838 21 405 15835 15849 15 406 15840 15857 18 407 15856 15898 43408 15900 15916 17 409 15931 15972 42 410 15988 16028 41 411 16030 1607546 412 16103 16164 62 413 16207 16243 37 414 16233 16246 14 415 1625516329 75 416 16349 16376 28 417 16378 16404 27 418 16399 16419 21 41916421 16461 41 420 16463 16479 17 421 16481 16503 23 422 16506 16579 74423 16582 16620 39 424 16622 16698 77 425 16700 16716 17 426 16723 1677149 427 16786 16816 31 428 16835 16864 30 429 16865 16878 14 430 1687216888 17 431 16890 16906 17 432 16904 16938 35 433 16965 17052 88 43417054 17069 16 435 17071 17085 15 436 17083 17098 16 437 17088 17111 24438 17124 17138 15 439 17140 17159 20 440 17181 17202 22 441 17202 1721817 442 17229 17248 20 443 17250 17268 19 444 17332 17349 18 445 1736317387 25 446 17389 17429 41 447 17450 17464 15 448 17482 17497 16 44918104 18117 14 450 18418 18431 14 451 18613 18626 14 452 18620 18634 15453 18707 18721 15 454 18841 18855 15 455 18875 18889 15 456 19282 1929514 457 19310 19323 14 458 19454 19467 14 459 19774 19792 19 460 1979419864 71 461 19862 19890 29 462 19892 19918 27 463 19907 19931 25 46419927 19942 16 465 19932 19971 40 466 19973 20011 39 467 20022 20063 42468 20080 20093 14 469 20131 20144 14 470 20240 20253 14 471 20448 2046316 472 20495 20508 14 473 20532 20545 14 474 20600 20613 14 475 2061720630 14 476 20960 20977 18 477 21412 21428 17 478 21465 21479 15 47921489 21508 20 480 21797 21812 16 481 22015 22030 16 482 22144 22157 14483 22153 22167 15 484 22265 22278 14 485 23110 23123 14 486 23114 2313320 487 23286 23303 18 488 23364 23379 16 489 23478 23498 21 490 2354423587 44 491 23589 23630 42 492 23658 23676 19 493 23678 23702 25 49423704 23729 26 495 23731 23748 18 496 23740 23755 16 497 23744 23757 14498 23750 23764 15 499 23767 23795 29 500 23802 23816 15 501 23818 2383114 502 23855 23869 15 503 23906 23926 21 504 23928 23942 15 505 2399424007 14 506 24005 24018 14 507 24023 24056 34 508 24074 24088 15 50924088 24104 17 510 24112 24163 52 511 24199 24212 14 512 24231 24244 14513 24237 24252 16 514 24254 24267 14 515 24281 24325 45 516 24327 2435327 517 24355 24374 20 518 24376 24399 24 519 24401 24416 16 520 2444224489 48 521 24492 24506 15 522 24498 24511 14 523 24538 24556 19 52424546 24562 17 525 24591 24618 28 526 24620 24633 14 527 24635 24650 16528 24665 24681 17 529 24687 24706 20 530 24709 24729 21 531 24731 2475222 532 24756 24771 16 533 24773 24788 16 534 24793 24821 29 535 2482324854 32 536 24856 24870 15 537 24873 24922 50 538 24933 24954 22 53924965 24984 20 540 25019 25052 34 541 25054 25099 46 542 25112 25125 14543 25133 25169 37 544 25171 25184 14 545 25186 25221 36 546 25236 2525318 547 25246 25296 51 548 25298 25336 39 549 25332 25348 17 550 2534925363 15 551 25388 25432 45 552 25439 25462 24 553 25509 25523 15 55425525 25547 23 555 25578 25593 16 556 25587 25601 15 557 25604 25617 14558 25633 25655 23 559 25672 25716 45 560 25725 25738 14 561 25764 2580037 562 25802 25828 27 563 25831 25846 16 564 25851 25872 22 565 2587725904 28 566 25921 25946 26 567 25943 25970 28 568 25972 25986 15 56926051 26064 14 570 26068 26086 19 571 26113 26137 25 572 26139 26159 21573 26182 26197 16 574 26243 26296 54 575 26298 26313 16 576 26327 2635024 577 26366 26385 20 578 26387 26404 18 579 26397 26415 19 580 2641626453 38 581 26447 26461 15 582 26457 26471 15 583 26481 26498 18 58426502 26525 24 585 26528 26562 35 586 26564 26590 27 587 26590 26622 33588 26624 26638 15 589 26687 26702 16 590 26706 26719 14 591 26717 2673014 592 26729 26743 15 593 26767 26797 31 594 26796 26816 21 595 2683126847 17 596 26837 26850 14 597 26877 26890 14 598 26900 26922 23 59926911 26933 23 600 26933 26946 14 601 26938 26977 40 602 26979 26992 14603 26981 27017 37 604 27023 27041 19 605 27039 27055 17 606 27075 2712147 607 27138 27153 16 608 27163 27266 104 609 27270 27293 24 610 2732527358 34 611 27363 27408 46 612 27419 27448 30 613 27450 27469 20 61427471 27498 28 615 27510 27523 14 616 27535 27562 28 617 28098 28119 22618 28136 28155 20 619 28169 28197 29 620 28199 28212 14 621 28221 2824424 622 28271 28285 15 623 28400 28414 15 624 28441 28476 36 625 2849028533 44 626 28535 28562 28 627 28575 28600 26 628 28621 28634 14 62928650 28663 14 630 28674 28687 14 631 28681 28699 19 632 28713 28730 18633 28736 28761 26 634 28763 28811 49 635 28821 28854 34 636 28856 2888126 637 28883 28920 38 638 28922 28947 26 639 28979 29006 28 640 2900829056 49 641 29078 29095 18 642 29098 29129 32 643 29122 29135 14 64429131 29144 14 645 29144 29158 15 646 29160 29207 48 647 29209 29230 22648 29234 29266 33 649 29268 29286 19 650 29301 29315 15 651 29304 2932320 652 29330 29352 23 653 29344 29358 15 654 29347 29365 19 655 2937729402 26 656 29402 29422 21 657 29424 29445 22 658 29443 29457 15 65929447 29460 14 660 29462 29475 14 661 29491 29512 22 662 29514 29551 38663 29547 29560 14 664 29553 29620 68 665 29625 29700 76 666 29714 2974532 667 29774 29805 32 668 29816 29847 32 669 29875 29892 18 670 2989429908 15 671 29897 29910 14 672 29917 29938 22 673 29939 29952 14 67429961 29976 16 675 29974 29987 14 676 29978 30001 24 677 30006 30023 18678 30025 30039 15 679 30043 30107 65 680 30145 30158 14 681 30149 3016618 682 30173 30228 56 683 30230 30250 21 684 30251 30309 59 685 3032130358 38 686 30359 30380 22 687 30382 30422 41 688 30428 30442 15 68930455 30482 28 690 30484 30498 15 691 30516 30531 16 692 30533 30646 114693 30654 30745 92 694 30745 30760 16 695 30752 30766 15 696 30788 3084356 697 30845 30867 23 698 30869 30912 44 699 30906 30920 15 700 3093430951 18 701 30962 30984 23 702 30989 31002 14 703 31010 31033 24 70431036 31062 27 705 31092 31106 15 706 31128 31166 39 707 31168 31182 15708 31189 31203 15 709 31205 31218 14 710 31224 31253 30 711 31256 3127217 712 31274 31292 19 713 31294 31322 29 714 31324 31353 30 715 3135731370 14 716 31373 31399 27 717 31403 31426 24 718 31445 31460 16 71931463 31483 21 720 31485 31501 17 721 31494 31508 15 722 31507 31529 23723 31531 31565 35 724 31567 31615 49 725 31630 31665 36 726 31675 3169117 727 31703 31721 19 728 31729 31769 41 729 31770 31790 21 730 3179531813 19 731 31815 31835 21 732 31837 31865 29 733 31876 31889 14 73431920 31945 26 735 31962 31978 17 736 31983 32014 32 737 32029 32050 22738 32058 32110 53 739 32129 32147 19 740 32166 32242 77 741 32244 3227936 742 32296 32315 20 743 32334 32396 63 744 32398 32425 28 745 3242732453 27 746 32459 32481 23 747 32475 32498 24 748 32490 32523 34 74932519 32534 16 750 32525 32547 23 751 32542 32555 14 752 32559 32572 14753 32574 32587 14 754 32595 32618 24 755 32613 32626 14 756 32627 3264923 757 32651 32664 14 758 32655 32689 35 759 32693 32719 27 760 3272132750 30 761 32752 32778 27 762 32780 32795 16 763 32797 32847 51 76432881 32894 14 765 32891 32904 14 766 32896 32911 16 767 32927 32972 46768 32986 33017 32 769 33019 33036 18 770 33038 33096 59 771 33102 3312322 772 33132 33145 14 773 33150 33163 14 774 33166 33199 34 775 3321433260 47 776 33262 33292 31 777 33294 33307 14 778 33316 33351 36 77933360 33402 43 780 33412 33425 14 781 33427 33442 16 782 33439 33452 14783 33443 33456 14 784 33460 33501 42 785 33503 33535 33 786 33542 3355716 787 34168 34181 14 788 34370 34385 16 789 35422 35435 14 790 3562735641 15 791 35685 35700 16 792 35837 35851 15 793 35849 35864 16 79435866 35879 14 795 35974 35987 14 796 36009 36042 34 797 36044 36079 36798 36081 36097 17 799 36099 36120 22 800 36119 36133 15 801 36147 3616317 802 36171 36200 30 803 36216 36241 26 804 36245 36274 30 805 3626536283 19 806 36295 36348 54 807 36352 36389 38 808 36383 36400 18 80936402 36419 18 810 36475 36520 46 811 36522 36539 18 812 36541 36626 86813 36652 36672 21 814 36675 36705 31 815 36707 36746 40 816 36780 3680829 817 36810 36823 14 818 36825 36901 77 819 36903 36922 20 820 3692436982 59 821 36999 37030 32 822 37056 37083 28 823 37091 37135 45 82437194 37221 28 825 37238 37277 40 826 37280 37294 15 827 37298 37315 18828 37325 37350 26 829 37363 37383 21 830 37377 37394 18 831 37384 3739714 832 37390 37438 49 833 37456 37481 26 834 37478 37491 14 835 3748137503 23 836 37506 37524 19 837 37526 37545 20 838 37540 37572 33 83937574 37590 17 840 37601 37616 16 841 37621 37658 38 842 37673 37690 18843 37703 37738 36 844 37740 37753 14 845 37764 37790 27 846 37800 3781819 847 37820 37850 31 848 37888 37909 22 849 37911 37972 62 850 3798638014 29 851 38016 38032 17 852 38034 38053 20 853 38055 38073 19 85438075 38090 16 855 38092 38128 37 856 38141 38167 27 857 38171 38194 24858 38213 38240 28 859 38264 38286 23 860 38288 38370 83 861 38394 3842027 862 38452 38467 16 863 38471 38487 17 864 38477 38490 14 865 3849438507 14 866 38536 38556 21 867 38580 38593 14 868 38602 38618 17 86938628 38654 27 870 38693 38709 17 871 38709 38722 14 872 38711 38725 15873 38740 38756 17 874 38749 38769 21 875 38772 38797 26 876 38827 3884620 877 38860 38883 24 878 38885 38905 21 879 38911 38931 21 880 3893338949 17 881 38962 39032 71 882 39034 39047 14 883 39049 39070 22 88439075 39115 41 885 39127 39143 17 886 39148 39162 15 887 39164 39222 59888 39218 39231 14 889 39224 39256 33 890 39265 39306 42 891 39297 3931115 892 39308 39343 36 893 39345 39359 15 894 39361 39381 21 895 3937039383 14 896 39383 39399 17 897 39417 39469 53 898 39490 39503 14 89939500 39522 23 900 39535 39549 15 901 39551 39611 61 902 39628 39647 20903 39649 39690 42 904 39707 39759 53 905 39773 39797 25 906 39799 3985860 907 39872 39928 57 908 39930 39969 40 909 39973 39997 25 910 3999840013 16 911 40015 40064 50 912 40067 40108 42 913 40110 40140 31 91440147 40163 17 915 40154 40179 26 916 40181 40196 16 917 40232 40282 51918 40284 40307 24 919 40309 40368 60 920 40381 40399 19 921 40431 4047141 922 40479 40493 15 923 40484 40522 39 924 40524 40544 21 925 4054740561 15 926 40577 40594 18 927 40586 40599 14 928 40616 40631 16 92940634 40647 14 930 40674 40727 54 931 40738 40755 18 932 40749 40771 23933 40780 40802 23 934 40811 40834 24 935 40847 40865 19 936 40861 4087515 937 40869 40897 29 938 40899 40919 21 939 40921 40939 19 940 4094240962 21 941 40967 40980 14 942 41008 41097 90 943 41099 41131 33 94441133 41200 68 945 41202 41223 22 946 41225 41242 18 947 41266 41279 14948 41275 41298 24 949 41300 41321 22 950 41325 41360 36 951 41367 4138822 952 41403 41421 19 953 41439 41462 24 954 41481 41496 16 955 4150841523 16 956 41531 41550 20 957 41552 41590 39 958 41590 41603 14 95941612 41662 51 960 41664 41688 25 961 41685 41698 14 962 41691 41716 26963 41718 41764 47 964 41761 41776 16 965 41778 41809 32 966 41798 4181114 967 41838 41866 29 968 41872 41893 22 969 41885 41898 14 970 4191241925 14 971 41914 41930 17 972 41923 41942 20 973 41933 41956 24 97441962 41978 17 975 41997 42012 16 976 42026 42042 17 977 42035 42048 14978 42037 42050 14 979 42048 42064 17 980 42056 42079 24 981 42081 4209515 982 42096 42139 44 983 42141 42187 47 984 42190 42226 37 985 4223242253 22 986 42255 42305 51 987 42307 42320 14 988 42347 42375 29 98942389 42425 37 990 42427 42442 16 991 42452 42474 23 992 42482 42496 15993 42495 42509 15 994 42536 42550 15 995 42566 42580 15 996 42590 4261223 997 42646 42678 33 998 42683 42723 41 999 42735 42750 16 1000 4275242817 66 1001 42843 42873 31 1002 42890 42939 50 1003 42938 42989 521004 42991 43005 15 1005 43007 43020 14 1006 43036 43055 20 1007 4305743102 46 1008 43113 43145 33 1009 43147 43180 34 1010 43204 43221 181011 43221 43265 45 1012 43267 43296 30 1013 43311 43334 24 1014 4333643361 26 1015 43371 43395 25 1016 43399 43423 25 1017 43425 43453 291018 43452 43468 17 1019 43470 43488 19 1020 43495 43522 28 1021 4352543559 35 1022 43561 43584 24 1023 43590 43611 22 1024 43618 43650 331025 43670 43685 16 1026 43722 43774 53 1027 43776 43791 16 1028 4380843835 28 1029 43835 43851 17 1030 43853 43868 16 1031 43923 43937 151032 43952 43987 36 1033 44011 44029 19 1034 44028 44070 43 1035 4407244094 23 1036 44101 44130 30 1037 44137 44205 69 1038 44224 44244 211039 44246 44265 20 1040 44267 44318 52 1041 44316 44336 21 1042 4433844359 22 1043 44361 44424 64 1044 44439 44474 36 1045 44476 44500 251046 44502 44519 18 1047 44539 44553 15 1048 44563 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113960 136 2932113962 114015 54 2933 114017 114048 32 2934 114045 114124 80 2935 114151114170 20 2936 114182 114218 37 2937 114230 114270 41 2938 114272 11429221 2939 114296 114339 44 2940 114354 114433 80 2941 114440 114457 182942 114459 114484 26 2943 114478 114536 59 2944 114538 114559 22 2945114567 114592 26 2946 114594 114610 17 2947 114612 114652 41 2948 114681114752 72 2949 114775 114805 31 2950 114803 114816 14 2951 114807 11482115 2952 114823 114847 25 2953 114868 114912 45 2954 114947 114961 152955 114974 114997 24 2956 115001 115015 15 2957 115004 115017 14 2958115019 115069 51 2959 115060 115073 14 2960 115072 115085 14 2961 115087115100 14 2962 115102 115124 23 2963 115132 115151 20 2964 115154 11516815 2965 115188 115208 21 2966 115219 115256 38 2967 115258 115283 262968 115285 115300 16 2969 115331 115353 23 2970 115355 115372 18 2971115380 115397 18 2972 115399 115412 14 2973 115426 115475 50 2974 115496115510 15 2975 115521 115545 25 2976 115555 115580 26 2977 115582 11560019 2978 115602 115621 20 2979 115653 115677 25 2980 115692 115720 292981 115722 115738 17 2982 115769 115783 15 2983 115792 115808 17 2984115819 115837 19 2985 115846 115878 33 2986 115888 115901 14 2987 115916115932 17 2988 115943 115956 14 2989 115967 115993 27 2990 115996 11601419 2991 116027 116045 19 2992 116105 116127 23 2993 116126 116139 142994 116141 116158 18 2995 116171 116186 16 2996 116194 116208 15 2997116257 116279 23 2998 116318 116373 56 2999 116375 116437 63 3000 116439116454 16 3001 116456 116496 41 3002 116500 116532 33 3003 116534 11655421 3004 116556 116573 18 3005 116575 116592 18 3006 116596 116615 203007 116617 116650 34 3008 116650 116664 15 3009 116666 116694 29 3010116775 116792 18 3011 116794 116811 18 3012 116813 116838 26 3013 116840116872 33 3014 116890 116911 22 3015 116921 116948 28 3016 116952 11698837 3017 116990 117006 17 3018 117008 117036 29 3019 117059 117133 753020 117187 117207 21 3021 117204 117217 14 3022 117209 117237 29 3023117239 117252 14 3024 117255 117275 21 3025 117277 117300 24 3026 117337117371 35 3027 117373 117416 44 3028 117418 117450 33 3029 117456 11750752 3030 117518 117532 15 3031 117534 117590 57 3032 117582 117604 233033 117593 117617 25 3034 117621 117648 28 3035 117640 117662 23 3036117664 117688 25 3037 117690 117711 22 3038 117728 117743 16 3039 117747117781 35 3040 117784 117801 18 3041 117792 117822 31 3042 117824 11784219 3043 117850 117869 20 3044 117890 117940 51 3045 117936 117968 333046 117970 117990 21 3047 117989 118034 46 3048 118034 118057 24 3049118061 118083 23 3050 118086 118122 37 3051 118122 118182 61 3052 118172118186 15 3053 118197 118211 15 3054 118216 118275 60 3055 118291 11831626 3056 118318 118354 37 3057 118373 118388 16 3058 118391 118405 153059 118407 118423 17 3060 118425 118456 32 3061 118465 118492 28 3062118498 118521 24 3063 118533 118551 19 3064 118553 118581 29 3065 118587118617 31 3066 118620 118679 60 3067 118687 118716 30 3068 118731 11877141 3069 118779 118805 27 3070 118816 118830 15 3071 118832 118895 643072 118910 119065 156 3073 119067 119081 15 3074 119095 119140 46 3075119170 119205 36 3076 119210 119232 23 3077 119230 119246 17 3078 119236119252 17 3079 119255 119274 20 3080 119271 119284 14 3081 119290 11930718 3082 119320 119335 16 3083 119357 119463 107 3084 119465 119483 193085 119485 119535 51 3086 119550 119571 22 3087 119577 119608 32 3088119610 119646 37 3089 119648 119688 41 3090 119713 119752 40 3091 119743119784 42 3092 119786 119800 15 3093 119822 119836 15 3094 119830 11984718 3095 119849 119900 52 3096 119912 119925 14 3097 119960 119982 233098 119984 120013 30 3099 120038 120054 17 3100 120057 120090 34 3101120092 120134 43 3102 120138 120154 17 3103 120157 120189 33 3104 120187120200 14 3105 120191 120211 21 3106 120225 120239 15 3107 120242 12026726 3108 120271 120301 31 3109 120320 120340 21 3110 120363 120406 443111 120406 120421 16 3112 120414 120468 55 3113 120457 120470 14 3114120487 120518 32 3115 120545 120563 19 3116 120567 120587 21 3117 120589120625 37 3118 120619 120633 15 3119 120650 120663 14 3120 120676 12069419 3121 120703 120717 15 3122 120721 120737 17 3123 120755 120812 583124 120816 120838 23 3125 120843 120871 29 3126 120873 120899 27 3127120903 120922 20 3128 120933 120946 14 3129 120936 120981 46 3130 120983121004 22 3131 121006 121021 16 3132 121023 121036 14 3133 121035 12106127 3134 121063 121079 17 3135 121081 121097 17 3136 121105 121134 303137 121138 121156 19 3138 121155 121168 14 3139 121158 121174 17 3140121166 121189 24 3141 121194 121208 15 3142 121201 121218 18 3143 121213121237 25 3144 121246 121271 26 3145 121298 121314 17 3146 121311 12132414 3147 121327 121351 25 3148 121359 121388 30 3149 121390 121419 303150 121446 121462 17 3151 121468 121487 20 3152 121499 121515 17 3153121517 121543 27 3154 121545 121564 20 3155 121575 121597 23 3156 121599121617 19 3157 121619 121662 44 3158 121664 121681 18 3159 121683 12170018 3160 121702 121751 50 3161 121773 121788 16 3162 121790 121805 163163 121807 121834 28 3164 121836 121857 22 3165 121859 121874 16 3166121877 121925 49 3167 121923 121936 14 3168 121928 121943 16 3169 121962121976 15 3170 121978 121992 15 3171 122004 122028 25 3172 122030 12205627 3173 122046 122059 14 3174 122052 122072 21 3175 122080 122095 163176 122099 122122 24 3177 122143 122163 21 3178 122169 122189 21 3179122258 122274 17 3180 122289 122309 21 3181 122311 122346 36 3182 122357122395 39 3183 122446 122468 23 3184 122471 122489 19 3185 122491 12251222 3186 122526 122541 16 3187 122543 122557 15 3188 122579 122592 143189 122606 122653 48 3190 122663 122690 28 3191 122728 122742 15 3192122757 122770 14 3193 122779 122840 62 3194 122842 122857 16 3195 122900122923 24 3196 122933 122955 23 3197 122968 123042 75 3198 123055 12307622 3199 123094 123108 15 3200 123114 123134 21 3201 123143 123160 183202 123162 123180 19 3203 123184 123198 15 3204 123200 123235 36 3205123237 123321 85 3206 123314 123329 16 3207 123342 123360 19 3208 123356123389 34 3209 123391 123410 20 3210 123412 123453 42 3211 123455 12348531 3212 123488 123503 16 3213 123506 123524 19 3214 123526 123543 183215 123545 123578 34 3216 123598 123634 37 3217 123654 123683 30 3218123685 123706 22 3219 123710 123774 65 3220 123803 123816 14 3221 123818123831 14 3222 123896 123939 44 3223 123941 123974 34 3224 123976 12402146 3225 124026 124040 15 3226 124042 124079 38 3227 124091 124109 193228 124158 124185 28 3229 124238 124274 37 3230 124319 124332 14 3231124335 124373 39 3232 124394 124412 19 3233 124419 124445 27 3234 124450124470 21 3235 124472 124493 22 3236 124499 124520 22 3237 124522 12456140 3238 124564 124595 32 3239 124607 124649 43 3240 124662 124729 683241 124750 124767 18 3242 124769 124793 25 3243 124812 124828 17 3244124853 124906 54 3245 124923 124948 26 3246 124958 124986 29 3247 125023125042 20 3248 125032 125046 15 3249 125065 125083 19 3250 125073 12509119 3251 125093 125107 15 3252 125132 125149 18 3253 125139 125154 163254 125151 125200 50 3255 125201 125274 74 3256 125314 125329 16 3257125331 125370 40 3258 125372 125386 15 3259 125411 125431 21 3260 125433125462 30 3261 125475 125562 88 3262 125564 125589 26 3263 125605 12563935 3264 125641 125699 59 3265 125719 125732 14 3266 125737 125769 333267 125815 125829 15 3268 125834 125848 15 3269 125850 125884 35 3270125899 125966 68 3271 125967 125999 33 3272 126026 126080 55 3273 126097126115 19 3274 126130 126149 20 3275 126151 126179 29 3276 126186 12623853 3277 126241 126279 39 3278 126275 126295 21 3279 126297 126312 163280 126320 126363 44 3281 126376 126395 20 3282 126406 126419 14 3283126420 126442 23 3284 126467 126501 35 3285 126503 126538 36 3286 126566126580 15 3287 126584 126597 14 3288 126620 126653 34 3289 126654 12669441 3290 126697 126715 19 3291 126764 126777 14 3292 126792 126828 373293 126842 126862 21 3294 126866 126879 14 3295 126881 126897 17 3296126906 126925 20 3297 126956 126987 32 3298 126989 127023 35 3299 127026127135 110 3300 127142 127174 33 3301 127176 127191 16 3302 127193127217 25 3303 127229 127253 25 3304 127255 127280 26 3305 127294 127394101 3306 127396 127415 20 3307 127417 127478 62 3308 127491 127504 143309 127506 127530 25 3310 127542 127566 25 3311 127582 127628 47 3312127654 127675 22 3313 127681 127706 26 3314 127706 127739 34 3315 127769127792 24 3316 127808 127829 22 3317 127839 127888 50 3318 127900 12793233 3319 127943 127975 33 3320 127988 128046 59 3321 128048 128069 223322 128068 128106 39 3323 128105 128118 14 3324 128121 128157 37 3325128159 128188 30 3326 128190 128268 79 3327 128279 128317 39 3328 128321128335 15 3329 128342 128368 27 3330 128374 128446 73 3331 128444 12854097 3332 128546 128586 41 3333 128588 128640 53 3334 128642 128674 333335 128675 128879 205 3336 128881 128936 56 3337 128934 129000 67 3338129002 129060 59 3339 129074 129100 27 3340 129107 129123 17 3341 129125129163 39 3342 129168 129230 63 3343 129264 129277 14 3344 129284 12931835 3345 129320 129346 27 3346 129357 129391 35 3347 129393 129420 283348 129447 129485 39 3349 129489 129504 16 3350 129514 129540 27 3351129550 129563 14 3352 129559 129595 37 3353 129606 129627 22 3354 129633129681 49 3355 129683 129697 15 3356 129699 129716 18 3357 129706 12973833 3358 129757 129790 34 3359 129792 129820 29 3360 129812 129846 353361 129851 129867 17 3362 129869 129883 15 3363 129885 129915 31 3364129917 129955 39 3365 129957 130046 90 3366 130042 130070 29 3367 130110130156 47 3368 130158 130309 152 3369 130311 130373 63 3370 130375130391 17 3371 130407 130429 23 3372 130439 130461 23 3373 130475 13050733 3374 130512 130550 39 3375 130552 130582 31 3376 130584 130614 313377 130616 130764 149 3378 130766 130869 104 3379 130871 131021 1513380 131033 131051 19 3381 131092 131105 14 3382 131112 131188 77 3383131194 131237 44 3384 131233 131247 15 3385 131236 131287 52 3386 131292131307 16 3387 131314 131333 20 3388 131373 131386 14 3389 131396 13141722 3390 131419 131439 21 3391 131429 131458 30 3392 131481 131499 193393 131676 131689 14 3394 131729 131743 15 3395 131745 131764 20 3396131785 131807 23 3397 131809 131875 67 3398 131877 131953 77 3399 131955131980 26 3400 132020 132068 49 3401 132086 132108 23 3402 132118 13213821 3403 132152 132183 32 3404 132185 132205 21 3405 132219 132232 143406 132234 132252 19 3407 132261 132291 31 3408 132319 132337 19 3409132345 132363 19 3410 132365 132378 14 3411 132414 132483 70 3412 132504132547 44 3413 132549 132582 34 3414 132584 132602 19 3415 132616 13264227 3416 132643 132681 39 3417 132685 132714 30 3418 132736 132769 343419 132771 132793 23 3420 132809 132825 17 3421 132827 132841 15 3422132861 132884 24 3423 132882 132900 19 3424 132899 132915 17 3425 132917132951 35 3426 132940 132954 15 3427 132958 132983 26 3428 132985 13303147 3429 133032 133051 20 3430 133042 133060 19 3431 133051 133071 213432 133073 133087 15 3433 133083 133104 22 3434 133097 133110 14 3435133131 133199 69 3436 133198 133222 25 3437 133233 133249 17 3438 133251133284 34 3439 133327 133429 103 3440 133431 133596 166 3441 133588133602 15 3442 133598 133611 14 3443 133613 133628 16 3444 133628 13364619 3445 133651 133670 20 3446 133666 133707 42 3447 133718 133742 253448 133743 133777 35 3449 133779 133794 16 3450 133821 133851 31 3451133859 133880 22 3452 133890 133921 32 3453 133923 133974 52 3454 133982133998 17 3455 134000 134036 37 3456 134065 134107 43 3457 134120 13417354 3458 134165 134179 15 3459 134187 134200 14 3460 134207 134242 363461 134244 134258 15 3462 134260 134273 14 3463 134275 134299 25 3464134314 134346 33 3465 134356 134371 16 3466 134365 134380 16 3467 134374134420 47 3468 134445 134477 33 3469 134508 134523 16 3470 134531 13454818 3471 134542 134555 14 3472 134568 134621 54 3473 134647 134667 213474 134679 134719 41 3475 134721 134824 104 3476 134826 134849 24 3477134856 134869 14 3478 134877 134910 34 3479 134912 134966 55 3480 134960134980 21 3481 134989 135012 24 3482 135014 135066 53 3483 135074 13509320 3484 135108 135125 18 3485 135151 135260 110 3486 135264 135277 143487 135273 135310 38 3488 135321 135337 17 3489 135340 135365 26 3490135360 135374 15 3491 135364 135386 23 3492 135388 135430 43 3493 135432135447 16 3494 135498 135521 24 3495 135519 135545 27 3496 135559 13562264 3497 135624 135647 24 3498 135656 135673 18 3499 135675 135704 303500 135721 135742 22 3501 135753 135796 44 3502 135815 135858 44 3503135860 135880 21 3504 135883 135915 33 3505 135922 135965 44 3506 135979135993 15 3507 135995 136036 42 3508 136051 136065 15 3509 136108 13616558 3510 136173 136190 18 3511 136192 136287 96 3512 136289 136303 153513 136317 136346 30 3514 136375 136415 41 3515 136429 136470 42 3516136472 136496 25 3517 136498 136532 35 3518 136542 136565 24 3519 136643136657 15 3520 136674 136701 28 3521 136704 136719 16 3522 136715 13672814 3523 136721 136737 17 3524 136737 136750 14 3525 136783 136810 283526 136824 136849 26 3527 136859 136896 38 3528 136898 136927 30 3529136949 136983 35 3530 136985 137000 16 3531 137053 137071 19 3532 137077137097 21 3533 137108 137164 57 3534 137166 137196 31 3535 137198 13722124 3536 137223 137267 45 3537 137276 137359 84 3538 137360 137385 263539 137393 137440 48 3540 137438 137496 59 3541 137498 137518 21 3542137523 137536 14 3543 137539 137572 34 3544 137584 137612 29 3545 137614137628 15 3546 137630 137644 15 3547 137646 137669 24 3548 137702 13772726 3549 137731 137745 15 3550 137759 137772 14 3551 137784 137819 363552 137832 137858 27 3553 137861 137876 16 3554 137878 137900 23 3555137909 137925 17 3556 137924 137961 38 3557 137968 137981 14 3558 138011138033 23 3559 138035 138077 43 3560 138079 138097 19 3561 138224 13823815 3562 138232 138252 21 3563 138242 138256 15 3564 138255 138284 303565 138295 138326 32 3566 138328 138357 30 3567 138359 138389 31 3568138403 138449 47 3569 138451 138492 42 3570 138500 138515 16 3571 138524138548 25 3572 138555 138568 14 3573 138571 138589 19 3574 138589 13862941 3575 138644 138680 37 3576 138697 138710 14 3577 138712 138729 183578 138744 138761 18 3579 138776 138801 26 3580 138860 138896 37 3581138898 138923 26 3582 138925 138965 41 3583 138967 139008 42 3584 139010139031 22 3585 139029 139043 15 3586 139034 139048 15 3587 139041 13905616 3588 139055 139074 20 3589 139078 139094 17 3590 139084 139098 153591 139092 139116 25 3592 139133 139147 15 3593 139154 139173 20 3594139175 139192 18 3595 139204 139229 26 3596 139231 139255 25 3597 139257139270 14 3598 139272 139303 32 3599 139315 139335 21 3600 139337 13937236 3601 139383 139397 15 3602 139399 139419 21 3603 139423 139437 153604 139435 139492 58 3605 139501 139518 18 3606 139508 139521 14 3607139571 139586 16 3608 139588 139622 35 3609 139636 139655 20 3610 139657139673 17 3611 139685 139699 15 3612 139724 139795 72 3613 139796 13981116 3614 139818 139834 17 3615 139836 139857 22 3616 139856 139869 143617 139859 139882 24 3618 139891 139920 30 3619 139930 139952 23 3620139965 139980 16 3621 139982 140011 30 3622 140013 140031 19 3623 140047140072 26 3624 140074 140099 26 3625 140101 140119 19 3626 140121 14013515 3627 140144 140158 15 3628 140157 140183 27 3629 140185 140210 263630 140231 140262 32 3631 140258 140272 15 3632 140264 140288 25 3633140290 140325 36 3634 140339 140364 26 3635 140369 140402 34 3636 140428140451 24 3637 140453 140510 58 3638 140512 140541 30 3639 140556 14062166 3640 140626 140651 26 3641 140653 140724 72 3642 140726 140789 643643 140802 140825 24 3644 140837 140861 25 3645 140863 140896 34 3646140903 140927 25 3647 140958 140993 36 3648 141001 141014 14 3649 141022141053 32

In some embodiments, the oligonucleotide comprises a contiguousnucleotide sequence of 10 to 30 nucleotides in length with at least 90%complementary, such as 100% complementarity, to a corresponding targetnucleic acid region present in SEQ ID NO: 1, wherein the target nucleicacid region is selected from the group consisting of region B1 to B400in table 2

TABLE 2 Regions of SEQ ID NO 1 which may be targeted usingoligonucleotide of the invention Position in SEQ ID NO 1 Reg. To FromLength B1 225 238 14 B2 1163 1178 16 B3 2526 2539 14 B4 2805 2820 16 B53027 3040 14 B6 3208 3222 15 B7 3212 3225 14 B8 3228 3241 14 B9 32433256 14 B10 3810 3854 45 B11 4664 4680 17 B12 5516 5529 14 B13 5657 567115 B14 5661 5676 16 B15 5964 5977 14 B16 6217 6234 18 B17 6224 6237 14B18 6408 6422 15 B19 7300 7313 14 B20 7399 7412 14 B21 7541 7564 24 B227626 7640 15 B23 7662 7694 33 B24 7791 7806 16 B25 7853 7868 16 B26 82068219 14 B27 8443 8456 14 B28 8739 8752 14 B29 9197 9212 16 B30 1018910203 15 B31 10754 10768 15 B32 10758 10771 14 B33 11790 11803 14 B3411870 11883 14 B35 11993 12007 15 B36 B11996 12011 16 B37 12017 12040 24B38 12095 12108 14 B39 12345 12358 14 B40 12721 12734 14 B41 13372 1338615 B42 13489 13505 17 B43 15576 15590 15 B44 15617 15632 16 B45 1584015853 14 B46 16041 16054 14 B47 16207 16222 16 B48 16308 16321 14 B4916349 16362 14 B50 16463 16479 17 B51 16528 16542 15 B52 16543 16556 14B53 20495 20508 14 B54 20617 20630 14 B55 20960 20977 18 B56 21465 2147915 B57 21491 21508 18 B58 23479 23496 18 B59 23741 23755 15 B60 2523625249 14 B61 25323 25336 14 B62 25447 25462 16 B63 25588 25601 14 B6425853 25867 15 B65 25885 25898 14 B66 26280 26293 14 B67 26388 26404 17B68 26416 26450 35 B69 26687 26702 16 B70 26706 26719 14 B71 26783 2679614 B72 27039 27052 14 B73 27251 27265 15 B74 28683 28698 16 B75 2930229315 14 B76 29304 29317 14 B77 29308 29321 14 B78 29532 29545 14 B7929974 29987 14 B80 30054 30068 15 B81 30267 30281 15 B82 30623 30638 16B83 30628 30641 14 B84 30814 30827 14 B85 30881 30894 14 B86 32459 3247820 B87 37299 37315 17 B88 39083 39096 14 B89 39370 39383 14 B90 3965939672 14 B91 40814 40831 18 B92 40851 40864 14 B93 41782 41795 14 B9441873 41886 14 B95 42037 42050 14 B96 42048 42063 16 B97 42096 42116 21B98 42959 42973 15 B99 43165 43178 14 B100 45926 45939 14 B101 4816348176 14 B102 52732 52745 14 B103 52984 53015 32 B104 54404 54420 17B105 55294 55320 27 B106 55337 55350 14 B107 55420 55434 15 B108 5548755501 15 B109 55623 55638 16 B110 56195 56214 20 B111 56584 56597 14B112 57267 57282 16 B113 58126 58139 14 B114 58170 58183 14 B115 5829558309 15 B116 58658 58671 14 B117 58906 58921 16 B118 58988 59005 18B119 59024 59045 22 B120 59191 59207 17 B121 59236 59251 16 B122 5929859312 15 B123 59358 59378 21 B124 59400 59413 14 B125 59434 59447 14B126 59589 59602 14 B127 59620 59642 23 B128 59718 59743 26 B129 5982659841 16 B130 59843 59864 22 B131 59882 59906 25 B132 59930 59958 29B133 59959 60004 46 B134 60006 60029 24 B135 60033 60071 39 B136 6013960171 33 B137 60193 60215 23 B138 60212 60225 14 B139 60231 60244 14B140 60246 60265 20 B141 60267 60282 16 B142 60292 60309 18 B143 6034860361 14 B144 60358 60429 72 B145 60427 60517 91 B146 60519 60545 27B147 60557 60575 19 B148 60580 60593 14 B149 60595 60622 28 B150 6067560690 16 B151 60697 60713 17 B152 60727 60754 28 B153 60756 60799 44B154 60801 60817 17 B155 60819 60855 37 B156 61423 61436 14 B157 6159261605 14 B158 61624 61637 14 B159 61673 61713 41 B160 61715 61731 17B161 61733 61752 20 B162 61769 61794 26 B163 61805 61825 21 B164 6210162114 14 B165 62302 62315 14 B166 62436 62449 14 B167 62664 62679 16B168 62993 63006 14 B169 63098 63111 14 B170 63347 63367 21 B171 6337163396 26 B172 63385 63398 14 B173 63526 63539 14 B174 65032 65045 14B175 66556 66569 14 B176 67158 67183 26 B177 67181 67194 14 B178 6800768021 15 B179 68644 68657 14 B180 69294 69317 24 B181 69306 69323 18B182 69353 69366 14 B183 70497 70511 15 B184 71600 71613 14 B185 7188771905 19 B186 72259 72272 14 B187 72589 72602 14 B188 72783 72796 14B189 73528 73541 14 B190 73783 73800 18 B191 74907 74920 14 B192 7596575981 17 B193 75983 75998 16 B194 76004 76020 17 B195 76110 76166 57B196 76186 76205 20 B197 76234 76253 20 B198 76261 76280 20 B199 7636976382 14 B200 77139 77152 14 B201 77409 77422 14 B202 77478 77524 47B203 77526 77590 65 B204 77628 77641 14 B205 77688 77701 14 B206 7827578308 34 B207 78310 78332 23 B208 78340 78356 17 B209 78358 78371 14B210 78373 78395 23 B211 78397 78440 44 B212 78442 78455 14 B213 7847578489 15 B214 78696 78709 14 B215 78847 78860 14 B216 79493 79516 24B217 79705 79718 14 B218 81009 81054 46 B219 81353 81367 15 B220 8197081986 17 B221 81991 82006 16 B222 82042 82106 65 B223 82278 82291 14B224 82716 82735 20 B225 84314 84328 15 B226 85628 85665 38 B227 8622686239 14 B228 86237 86253 17 B229 86566 86579 14 B230 86945 86959 15B231 87337 87358 22 B232 87662 87675 14 B233 89424 89439 16 B234 8997289985 14 B235 90782 90795 14 B236 90939 90953 15 B237 90942 90955 14B238 90965 90981 17 B239 91101 91115 15 B240 92083 92096 14 B241 9216492177 14 B242 92179 92192 14 B243 92194 92210 17 B244 92212 92236 25B245 92245 92260 16 B246 92262 92302 41 B247 92304 92321 18 B248 9232392366 44 B249 92375 92389 15 B250 92392 92405 14 B251 92407 92426 20B252 92442 92459 18 B253 92497 92516 20 B254 92578 92591 14 B255 9259992612 14 B256 92614 92651 38 B257 92659 92684 26 B258 92686 92699 14B259 92704 92726 23 B260 92731 92750 20 B261 92752 92774 23 B262 9278092795 16 B263 92800 92813 14 B264 92839 92858 20 B265 92860 92891 32B266 92893 92906 14 B267 92908 92921 14 B268 92923 92941 19 B269 9296592986 22 B270 92988 93002 15 B271 93044 93059 16 B272 93061 93076 16B273 93105 93122 18 B274 93142 93209 68 B275 93227 93241 15 B276 9328893305 18 B277 93325 93344 20 B278 93398 93412 15 B279 93572 93586 15B280 94509 94522 14 B281 95720 95738 19 B282 97050 97065 16 B283 9707997098 20 B284 97127 97194 68 B285 97208 97230 23 B286 97232 97284 53B287 97286 97311 26 B288 97313 97362 50 B289 97368 97383 16 B290 9742697439 14 B291 98077 98090 14 B292 98227 98240 14 B293 98232 98255 24B294 99151 99164 14 B295 99405 99418 14 B296 99570 99583 14 B297 9973399748 16 B298 101829 101842 14 B299 101882 101895 14 B300 101955 10196814 B301 102202 102215 14 B302 103310 103325 16 B303 103653 103666 14B304 103908 103923 16 B305 103912 103928 17 B306 103917 103933 17 B307104971 104984 14 B308 105217 105230 14 B309 105233 105250 18 B310 105443105457 15 B311 105544 105559 16 B312 106047 106071 25 B313 106061 10607414 B314 106093 106107 15 B315 106114 106130 17 B316 106243 106256 14B317 106251 106264 14 B318 106840 106855 16 B319 108113 108130 18 B320108325 108338 14 B321 108856 108869 14 B322 109109 109122 14 B323 109113109127 15 B324 109116 109132 17 B325 110301 110314 14 B326 110315 11032814 B327 110317 110330 14 B328 112528 112546 19 B329 112607 112620 14B330 114775 114788 14 B331 116322 116335 14 B332 116968 116981 14 B333117788 117801 14 B334 118034 118057 24 B335 118230 118246 17 B336 118235118248 14 B337 118870 118883 14 B338 119755 119784 30 B339 119786 11980015 B340 120363 120406 44 B341 120504 120517 14 B342 121161 121174 14B343 121330 121347 18 B344 121338 121351 14 B345 123417 123430 14 B346123464 123481 18 B347 125026 125042 17 B348 127046 127071 26 B349 127090127103 14 B350 127311 127324 14 B351 127354 127367 14 B352 127363 12737917 B353 127399 127412 14 B354 127863 127876 14 B355 128134 128148 15B356 128280 128310 31 B357 128343 128368 26 B358 128444 128457 14 B359128446 128469 24 B360 128498 128511 14 B361 128511 128524 14 B362 129892129905 14 B363 130261 130283 23 B364 130375 130388 14 B365 130415 13042814 B366 130634 130650 17 B367 130667 130717 51 B368 130719 130764 46B369 130783 130796 14 B370 130798 130820 23 B371 130840 130861 22 B372130975 130994 20 B373 131112 131132 21 B374 131142 131161 20 B375 131233131246 14 B376 131729 131743 15 B377 132754 132767 14 B378 132924 13293714 B379 133174 133190 17 B380 133198 133212 15 B381 133207 133222 16B382 133476 133489 14 B383 133479 133492 14 B384 133491 133531 41 B385133533 133550 18 B386 133555 133594 40 B387 134160 134173 14 B388 134165134178 14 B389 134533 134546 14 B390 136724 136737 14 B391 137438 13746326 B392 137878 137891 14 B393 138082 138097 16 B394 138233 138252 20B395 138930 138943 14 B396 138947 138960 14 B397 138950 138963 14 B398139502 139518 17 B399 139508 139521 14 B400 140978 140991 14

In certain embodiments the oligonucleotide or contiguous nucleotidesequence is complementary to a region (or sub-sequence)(or sub-sequence)of the target nucleic acid, wherein the target nucleic acid region isselected from the group consisting of position 1589-10889, 46089-53989and 60789-62489 of SEQ ID NO: 1.

In one embodiment the oligonucleotide comprises a contiguous nucleotidesequence of 10 to 30 nucleotides in length with at least 90%, such as100% complementary to a target nucleic acid sequence of position 55319to 141053 of SEQ ID NO: 1.

In one embodiment the oligonucleotide comprises a contiguous nucleotidesequence of 10 to 30 nucleotides in length with at least 90%, such as100% complementary to a target nucleic acid sequence of position 1 to55318 of SEQ ID NO: 1.

In some embodiments, the oligonucleotide comprises a contiguousnucleotide sequence of 10 to 30 nucleotides in length with at least 90%complementary to a sub-sequence of the target nucleic acid selected fromthe group corresponding to positions: 55319-76274, 77483-77573,92157-93403 and 97056-97354 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid selected from the groupcorresponding to positions: 60821-60849, 77567-77583, 92323-92339 and97156-97172 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid corresponding to positions:5218-5240 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid corresponding to positions:5782-5803 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid corresponding to positions:8113-8139 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid corresponding to positions:9200-9250 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid corresponding to positions:11505-11555 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid corresponding to positions:13223-13242 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid corresponding to positions15100-15150 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid corresponding to positions15113-15180 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid corresponding to positions29635-29705 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid corresponding to positions30590-30740 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid corresponding to positions39800-39855 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid to positions 44435-44460 of SEQID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid to positions 45245-45270 of SEQID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid to positions 46380-46430 of SEQID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequenceof 10 to 30 nucleotides in length with at least 90% complementary to asub-sequence of the target nucleic acid to positions 68915-68940 of SEQID NO: 1.

In some embodiments, the oligonucleotide comprises or consists of 8 to35 nucleotides in length, such as from 10 to 30, such as 11 to 22, suchas from 12 to 18, such as from 13 to 17 or 14 to 16 contiguousnucleotides in length. In a preferred embodiment, the oligonucleotidecomprises or consists of 15 to 20 nucleotides in length.

In some embodiments, the oligonucleotide or contiguous nucleotidesequence thereof comprises or consists of 22 or less nucleotides, suchas 20 or less nucleotides, such as 18 or less nucleotides, such as 14,15, 16 or 17 nucleotides. It is to be understood that any range givenherein includes the range endpoints. Accordingly, if an oligonucleotideis said to include from 10 to 30 nucleotides, both 10 and 30 nucleotidesare included.

In some embodiments, the contiguous nucleotide sequence comprises orconsists of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29 or 30 contiguous nucleotides in length. In apreferred embodiment, the oligonucleotide comprises or consists of 16,17, 18 or 19 nucleotides in length.

In some embodiments, the antisense oligonucleotide or contiguousnucleotide sequence comprises or consists of 10 to 30 nucleotides inlength with at least 90% identity, preferably 100% identity to asequence selected from the group consisting of SEQ ID NO: 4 to 150 (seemotif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguousnucleotide sequence comprises or consists of 10 to 30 nucleotides inlength with at least 90% identity, preferably 100% identity to asequence selected from the group consisting of SEQ ID NO: 4 to 818 (seemotif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguousnucleotide sequence comprises or consists of 10 to 30 nucleotides inlength with at least 90% identity, preferably 100% identity to asequence selected from the group consisting of SEQ ID NO: 4 to 678 (seemotif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguousnucleotide sequence comprises or consists of 10 to 30 nucleotides inlength with at least 90% identity, preferably 100% identity to asequence selected from the group consisting of SEQ ID NO: 166, 167, 167or 169 (see motif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguousnucleotide sequence comprises or consists of 10 to 30 nucleotides inlength with at least 90% identity, preferably 100% identity to asequence selected from the group consisting of SEQ ID NO: 570, 571, 572,679, 680, 681, 682 and 683 (see motif sequences listed in table 3 in theExamples section).

In some embodiments, the antisense oligonucleotide or contiguousnucleotide sequence comprises or consists of 10 to 30 nucleotides inlength with at least 90% identity, preferably 100% identity to asequence selected from the group consisting of SEQ ID NO: 34, 186, 187,188, 573, 574, 575, 576, 572, 684, 685, 686, 687, 688, 689, 690, 691,692, 963, 964, 965 and 696 (see motif sequences listed in table 3 in theExamples section).

In some embodiments, the antisense oligonucleotide or contiguousnucleotide sequence comprises or consists of 10 to 30 nucleotides inlength with at least 90% identity, preferably 100% identity to asequence selected from the group consisting of SEQ ID NO: 35, 199, 200,201, 202, 203, 204, 205, 206, 207, 209 and 210 or SEQ ID NO: 582, 583and 584 (see motif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguousnucleotide sequence comprises or consists of 10 to 30 nucleotides inlength with at least 90% identity, preferably 100% identity to asequence selected from the group consisting of SEQ ID NO: 221, 222, 223,224, 225, 585, 586, 587, 588, 589, 698, 699, 700, 701, 702, 703, 704,705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717 and 718(see motif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguousnucleotide sequence comprises or consists of 10 to 30 nucleotides inlength with at least 90% identity, preferably 100% identity to asequence selected from the group consisting of SEQ ID NO: 236, 237, 238,239, 240 and 590.

In some embodiments, the antisense oligonucleotide or contiguousnucleotide sequence comprises or consists of 10 to 30 nucleotides inlength with at least 90% identity, preferably 100% identity to asequence selected from the group consisting of SEQ ID NO: 241, 591 and719 (see motif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguousnucleotide sequence comprises or consists of 10 to 30 nucleotides inlength with at least 90% identity, preferably 100% identity to asequence selected from the group consisting of SEQ ID NO: 46, 47, 48,285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298,299, 300, 301, 302, 303, 304, 305, 613, 614, 615, 616, 617, 618, 619,620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 721,722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 734, 735, 736,737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750,751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764,765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778,779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792,793, 794, 795, 796, 797, 798, 799, 800, 800, 800, 800, 800, 801, 801,802, 803, 804, 805, 806 and 807 (see motif sequences listed in table 3in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguousnucleotide sequence comprises or consists of 10 to 30 nucleotides inlength with at least 90% identity, preferably 100% identity to asequence selected from the group consisting of SEQ ID NO: 331, 332, 638,639, 640, 808, 809, 810, 811, 812, 813, 814 and 815 (see motif sequenceslisted in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguousnucleotide sequence comprises or consists of 10 to 30 nucleotides inlength with at least 90% identity, preferably 100% identity to asequence selected from the group consisting of SEQ ID NO: 409, 410, 411,642, 643, 644, 645, 646, 816, 818 and 818 (see motif sequences listed intable 3 in the Examples section).

It is understood that the contiguous nucleobase sequences (motifsequence) can be modified to for example increase nuclease resistanceand/or binding affinity to the target nucleic acid. Modifications aredescribed in the definitions and in the “Oligonucleotide design”section. Table 3 lists preferred designs of each motif sequence.

Oligonucleotide Design

Oligonucleotide design refers to the pattern of nucleoside sugarmodifications in the oligonucleotide sequence. The oligonucleotides ofthe invention comprise sugar-modified nucleosides and may also compriseDNA or RNA nucleosides. In some embodiments, the oligonucleotidecomprises sugar-modified nucleosides and DNA nucleosides. Incorporationof modified nucleosides into the oligonucleotide of the invention mayenhance the affinity of the oligonucleotide for the target nucleic acid.In that case, the modified nucleosides can be referred to as affinityenhancing modified nucleotides.

In an embodiment, the oligonucleotide comprises at least 1 modifiednucleoside, such as at least 2, at least 3, at least 4, at least 5, atleast 6, at least 7, at least 8, at least 9, at least 10, at least 11,at least 12, at least 13, at least 14, at least 15 or at least 16modified nucleosides. In an embodiment the oligonucleotide comprisesfrom 1 to 10 modified nucleosides, such as from 2 to 9 modifiednucleosides, such as from 3 to 8 modified nucleosides, such as from 4 to7 modified nucleosides, such as 6 or 7 modified nucleosides. In someembodiments, at least 1 of the modified nucleosides is a locked nucleicacid (LNA), such as at least 2, such as at least 3, at least 4, at least5, at least 6, at least 7, or at least 8 of the modified nucleosides areLNA. In a still further embodiment all the modified nucleosides are LNA.

In an embodiment, the oligonucleotide of the invention may comprisemodifications, which are independently selected from these three typesof modifications (modified sugar, modified nucleobase and modifiedinternucleoside linkage) or a combination thereof. Preferably theoligonucleotide comprises one or more sugar modified nucleosides, suchas 2′ sugar modified nucleosides. Preferably the oligonucleotide of theinvention comprise the one or more 2′ sugar modified nucleosideindependently selected from the group consisting of 2′-O-alkyl-RNA,2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA, 2′-amino-DNA,2′-fluoro-DNA, arabino nucleic acid (ANA), 2′-fluoro-ANA and LNAnucleosides. Even more preferably the one or more modified nucleoside isLNA.

In a further embodiment the oligonucleotide comprises at least onemodified internucleoside linkage. In a preferred embodiment theinternucleoside linkages within the contiguous nucleotide sequence arephosphorothioate or boranophosphate internucleoside linkages.

In some embodiments, the oligonucleotide of the invention comprise atleast one modified nucleoside which is a 2′-MOE-RNA, such as 2, 3, 4, 5,6, 7, 8, 9 or 10 2′-MOE-RNA nucleoside units. In some embodiments, atleast one of said modified nucleoside is 2′-fluoro DNA, such as 2, 3, 4,5, 6, 7, 8, 9 or 10 2′-fluoro-DNA nucleoside units.

In some embodiments, the oligonucleotide of the invention comprises atleast one LNA unit, such as 1, 2, 3, 4, 5, 6, 7, or 8 LNA units, such asfrom 2 to 6 LNA units, such as from 3 to 7 LNA units, 4 to 8 LNA unitsor 3, 4, 5, 6 or 7 LNA units. In some embodiments, all the modifiednucleosides are LNA nucleosides. In a further embodiment, theoligonucleotide may comprise both beta-D-oxy-LNA, and one or more of thefollowing LNA units: thio-LNA, amino-LNA, oxy-LNA, and/or ENA in eitherthe beta-D or alpha-L configurations or combinations thereof. In afurther embodiment, all LNA cytosine units are 5-methyl-cytosine. In apreferred embodiment the oligonucleotide or contiguous nucleotidesequence has at least 1 LNA unit at the 5′ end and at least 2 LNA unitsat the 3′ end of the nucleotide sequence.

In some embodiments, the oligonucleotide of the invention comprises atleast one LNA unit and at least one 2′ substituted modified nucleoside.

In some embodiments of the invention, the oligonucleotide comprise both2′ sugar modified nucleosides and DNA units. Preferably theoligonucleotide comprise both LNA and DNA units. Preferably, thecombined total of LNA and DNA units is 8-30, such as 10-25, preferably12-22, such as 12-18, even more preferably 11-16. In some embodiments ofthe invention, the nucleotide sequence of the oligonucleotide, such asthe contiguous nucleotide sequence consists of at least one or two LNAunits and the remaining nucleotide units are DNA units. In someembodiments the oligonucleotide comprises only LNA nucleosides andnaturally occurring nucleosides (such as RNA or DNA, most preferably DNAnucleosides), optionally with modified internucleoside linkages such asphosphorothioate.

In an embodiment of the invention the oligonucleotide of the inventionis capable of recruiting RNase H.

Gapmer Design

In a preferred embodiment the oligonucleotide of the invention has agapmer design or structure also referred herein merely as “Gapmer”. In agapmer structure the oligonucleotide comprises at least three distinctstructural regions a 5′-flank, a gap and a 3′-flank, F-G-F′ in ′5→3′orientation. In this design, flanking regions F and F′ (also termed wingregions) comprise a contiguous stretch of modified nucleosides, whichare complementary to the UBE3A target nucleic acid, while the gapregion, G, comprises a contiguous stretch of nucleotides which arecapable of recruiting a nuclease, preferably an endonuclease such asRNase, for example RNase H, when the oligonucleotide is in duplex withthe target nucleic acid. Nucleosides which are capable of recruiting anuclease, in particular RNase H, can be selected from the groupconsisting of DNA, alpha-L-oxy-LNA, 2′-Flouro-ANA and UNA. Regions F andF′, flanking the 5′ and 3′ ends of region G, preferably comprisenon-nuclease recruiting nucleosides (nucleosides with a 3′ endostructure), more preferably one or more affinity enhancing modifiednucleosides. In some embodiments, the 3′ flank comprises at least oneLNA nucleoside, preferably at least 2 LNA nucleosides. In someembodiments, the 5′ flank comprises at least one LNA nucleoside. In someembodiments both the 5′ and 3′ flanking regions comprise a LNAnucleoside. In some embodiments all the nucleosides in the flankingregions are LNA nucleosides. In other embodiments, the flanking regionsmay comprise both LNA nucleosides and other nucleosides (mixed flanks),such as DNA nucleosides and/or non-LNA modified nucleosides, such as 2′substituted nucleosides. In this case the gap is defined as a contiguoussequence of at least 5 RNase H recruiting nucleosides (nucleosides witha 2′ endo structure, preferably DNA) flanked at the 5′ and 3′ end by anaffinity enhancing modified nucleoside, preferably LNA, such asbeta-D-oxy-LNA. Consequently, the nucleosides of the 5′ flanking regionand the 3′ flanking region which are adjacent to the gap region aremodified nucleosides, preferably non-nuclease recruiting nucleosides. Inoligonucleotides with mixed flanks where the flanks comprise DNA the 5′and 3′ nucleosides are modified nucleosides.

Region F

Region F (5′ flank or 5′ wing) attached to the ′5 end of region Gcomprises, contains or consists of at least one modified nucleoside suchas at least 2, at least 3, at least 4, at least 5, at least 6, at least7 modified nucleosides. In an embodiment region F comprises or consistsof from 1 to 7 modified nucleosides, such as from 2 to 6 modifiednucleosides, such as from 2 to 5 modified nucleosides, such as from 2 to4 modified nucleosides, such as from 1 to 3 modified nucleosides, suchas 1, 2, 3 or 4 modified nucleosides. In a further embodiment furtheradditional nucleosides may be attached to the ′5 end of region F,representing a region D preferably comprising 1, 2 or 3 nucleosideunits, such as DNA nucleosides. Region D can take the function of abiocleavable (B) linker described in the definition of “Linkers”.

In some embodiments, the modified nucleosides in region F have a 3′ endostructure.

In an embodiment, one or more of the modified nucleosides in region Fare 2′ modified nucleosides.

In a further embodiment one or more of the 2′ modified nucleosides inregion F are selected from 2′-O-alkyl-RNA units, 2′-O-methyl-RNA,2′-amino-DNA units, 2′-fluoro-DNA units, 2′-alkoxy-RNA, MOE units, LNAunits, arabino nucleic acid (ANA) units and 2′-fluoro-ANA units.

In one embodiment of the invention all the modified nucleosides inregion F are LNA nucleosides. In a further embodiment the LNAnucleosides in region F are independently selected from the groupconsisting of oxy-LNA, thio-LNA, amino-LNA, cET, and/or ENA, in eitherthe beta-D or alpha-L configurations or combinations thereof. In apreferred embodiment region F has at least 1 beta-D-oxy LNA unit, at the5′ end of the contiguous sequence.

Region G

Region G (gap region) preferably comprise, contain or consist of atleast 4, such as at least 5, such as at least 6, at least 7, at least 8,at least 9, at least 10, at least 11, at least 12, at least 13, at least14, at least 15 or at least 16 consecutive nucleosides capable ofrecruiting the aforementioned nuclease, in particular RNaseH. In afurther embodiment region G comprise, contain or consist of from 5 to12, or from 6 to 10 or from 7 to 9, such as 8 consecutive nucleotideunits capable of recruiting aforementioned nuclease.

The nucleoside units in region G, which are capable of recruitingnuclease are in an embodiment selected from the group consisting of DNA,alpha-L-LNA, C4′ alkylated DNA (as described in PCT/EP2009/050349 andVester et al., Bioorg. Med. Chem. Lett. 18 (2008) 2296-2300, bothincorporated herein by reference), arabinose derived nucleosides likeANA and 2′F-ANA (Mangos et al. 2003 J. AM. CHEM. SOC. 125, 654-661), UNA(unlocked nucleic acid) (as described in Fluiter et al., Mol. Biosyst.,2009, 10, 1039 incorporated herein by reference). UNA is unlockednucleic acid, typically where the bond between C2 and C3 of the ribosehas been removed, forming an unlocked “sugar” residue.

In a still further embodiment at least one nucleoside unit in region Gis a DNA nucleoside unit, such as from 1 to 16 DNA units, such as 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 DNA units, preferably from 2to 13 DNA units, such as from 4 to 12 DNA units, more preferably from 5to 11, or from 10 to 16, 11 to 15 or 12 to 14 DNA units. In someembodiments, region G consists of 100% DNA units. In a preferredembodiment G consists of, most preferably 10, 11, 12, 13, 14 or 15 DNAunits.

In further embodiments the region G may consist of a mixture of DNA andother nucleosides capable of mediating RNase H cleavage. Region G mayconsist of at least 50% DNA, more preferably 60%, 70% or 80% DNA, andeven more preferred 90% or 95% DNA.

In a still further embodiment at least one nucleoside unit in region Gis an alpha-L-LNA nucleoside unit, such as at least one alpha-L-LNAunit, such as 2, 3, 4, 5, 6, 7, 8 or 9 alpha-L-LNA units. In a furtherembodiment, region G comprises the least one alpha-L-LNA isalpha-L-oxy-LNA unit. In a further embodiment region G comprises acombination of DNA and alpha-L-LNA nucleoside units.

In some embodiments the size of the contiguous sequence in region G maybe longer, such as 15, 16, 17, 18, 19 or 20 nucleoside units.

In some embodiments, nucleosides in region G have a 2′ endo structure.

Region F′

Region F′ (3′ flank or 3′ wing) attached to the ′3 end of region Gcomprises, contains or consists of at least one modified nucleoside suchas at least 2, at least 3, at least 4, at least 5, at least 6, at least7 modified nucleosides. In an embodiment region F′ comprise or consistof from 1 to 7 modified nucleosides, such as from 2 to 6 modifiednucleoside, such as from 2 to 4 modified nucleosides, such as from 1 to3 modified nucleosides, such as 1, 2, 3 or 4 modified nucleosides. In afurther embodiment further additional nucleosides attached to the ′3 endof region F′, representing a region D′, preferably comprising 1, 2 or 3nucleoside units, such as DNA nucleosides. Region D′ can take thefunction of a biocleavable (B) linker described, in the section“Linkers”.

In some embodiments, the modified nucleosides in region F′ have a 3′endo structure.

In a preferred embodiment, modified nucleosides in region F′ is LNA.

In a further embodiment modified nucleosides in region F′ are selectedfrom 2′-O-alkyl-RNA units, 2′-O-methyl-RNA, 2′-amino-DNA units,2′-fluoro-DNA units, 2′-alkoxy-RNA, MOE units, LNA units, arabinonucleic acid (ANA) units and 2′-fluoro-ANA units.

In one embodiment of the invention all the modified nucleosides inregion F′ are LNA nucleosides. In a further embodiment the LNAnucleosides in region F′ are independently selected from the groupconsisting of oxy-LNA, thio-LNA, amino-LNA, cET and/or ENA, in eitherthe beta-D or alpha-L configurations or combinations thereof. In apreferred embodiment region F′ has at least 2 beta-D-oxy LNA unit, atthe 3′ end of the contiguous sequence.

Region D and D′

Region D and D′ can be attached to the 5′ end of region F or the 3′ endof region F′, respectively.

Region D or D′ may independently comprise 1, 2, 3, 4 or 5 additionalnucleotides, which may be complementary or non-complementary to thetarget nucleic acid. In this respect the oligonucleotide of theinvention, may in some embodiments comprise a contiguous nucleotidesequence capable of modulating the target which is flanked at the 5′and/or 3′ end by additional nucleotides. Such additional nucleotides mayserve as a nuclease susceptible biocleavable linker (see definition oflinkers). In some embodiments the additional 5′ and/or 3′ endnucleotides are linked with phosphodiester linkages, and may be DNA orRNA. In another embodiment, the additional 5′ and/or 3′ end nucleotidesare modified nucleotides which may for example be included to enhancenuclease stability or for ease of synthesis. In an embodiment of theoligonucleotide of the invention, comprises a region D and/or D′ inaddition to the contiguous nucleotide sequence.

The gapmer oligonucleotide of the present invention can be representedby the following formulae:F-G-F′; in particular F₁₋₇-G₄₋₁₂-F′₁₋₇D-F-G-F′, in particular D₁₋₃-F₁₋₇-G₄₋₁₂-F′₁₋₇F-G-F′-D′, in particular F₁₋₇-G₄₋₁₂-F′₁₋₇-D′₁₋₃D-F-G-F′-D′, in particular D₁₋₃-F₁₋₇-G₄₋₁₂-F′₁₋₇-D′₁₋₃

The preferred number and types of nucleosides in regions F, G and F′, Dand D′ have been described above. The design of the individualoligonucleotide may also have profound impact on the properties of theoligonucleotide in its use for modulating expression of UBE3A.

In some embodiments the oligonucleotide is a gapmer consisting of 14,15, 16, 17, 18, 19 or 20 nucleotides in length, wherein each of regionsF and F′ independently consists of 2, 3 or 4 modified nucleoside unitscomplementary to a part of the human SNHG14 long non-coding RNA which isantisense to the UBE3A pre-mRNA (the target nucleic acid) and region Gconsists of 10, 11, 12, 13, 14 or 15 nucleoside units, capable ofrecruiting nuclease when in duplex with the target nucleic acid.

In a further embodiments, the oligonucleotide is a gapmer wherein eachof regions F and F′ independently consists of 2, 3, 4 or 5 modifiednucleoside units, such as nucleoside units containing a2′-O-methoxyethyl-ribose sugar (2′-MOE) or nucleoside units containing a2′-fluoro-deoxyribose sugar and/or LNA units, and region G consists of9, 10, 11, 12, 13, 14 or 15 nucleoside units, such as DNA units or othernuclease recruiting nucleosides such as alpha-L-LNA or a mixture of DNAand nuclease recruiting nucleosides.

In a further specific embodiment, the oligonucleotide is a gapmerwherein each of regions F and F′ region consists of two LNA units each,and region G consists of 10, 11, 12, 13, 14 or 15 nucleoside units,preferably DNA units. Specific gapmer designs of this nature include2-10-2, 2-11-2, 2-12-2, 2-13-2, 2-14-2 and 2-15-2.

In a further specific embodiment, the oligonucleotide is a gapmerwherein each of regions F and F′ independently consists of three LNAunits, and region G consists of 10, 11, 12, 13, 14 or 15 nucleosideunits, preferably DNA units. Specific gapmer designs of this natureinclude 3-10-3, 3-11-3, 3-12-3, 3-13-3, 3-14-3 and 3-15-3.

In a further specific embodiment, the oligonucleotide is a gapmerwherein each of regions F and F′ consists of four LNA units each, andregion G consists of 10, 11, 12, 13, 14 or 15 nucleoside units,preferably DNA units. Specific gapmer designs of this nature include4-10-4, 4-11-4, 4-12-4, 4-13-4, 4-14-4 and 4-15-4.

Specific gapmer designs of this nature include F-G-F′ designs selectedfrom a group consisting of a gap with 10 nucleosides and independently 1to 4 modified nucleosides in the wings including 1-10-1, 2-10-1, 1-10-2,1-10-3, 3-10-1, 1-10-4, 4-10-1, 2-10-2, 2-10-3, 3-10-2, 2-10-4, 4-10-2,3-10-3, 3-10-4, 4-10-3 and 4-10-4 gapmers.

Specific gapmer designs of this nature include F-G-F′ designs selectedfrom a group consisting of a gap with 11 nucleosides and independently 1to 4 modified nucleosides in the wings including, 1-11-1, 2-11-1,1-11-2, 1-11-3, 3-11-1, 1-11-4, 4-11-1, 2-11-2, 2-11-3, 3-11-2, 2-11-4,4-11-2, 3-11-3, 3-11-4, 4-11-3 and 4-11-4 gapmers.

Specific gapmer designs of this nature include F-G-F′ designs selectedfrom a group consisting of a gap with 12 nucleosides including, 1-12-1,2-12-1, 1-12-2, 1-12-3, 3-12-1, 1-12-4, 4-12-1, 2-12-2, 2-12-3, 3-12-2,2-12-4, 4-12-2, 3-12-3, 3-12-4, 4-12-3 and 4-12-4 gapmers.

Specific gapmer designs of this nature include F-G-F′ designs selectedfrom a group consisting of a gap with 13 nucleosides and independently 1to 4 modified nucleosides in the wings including 1-13-1, 1-13-2, 1-13-3,3-13-1, 1-13-4, 4-13-1, 2-13-1, 2-13-2, 2-13-3, 3-13-2, 2-13-4, 4-13-2,3-13-3, 3-13-4, 4-13-3, and 4-13-4 gapmers.

Specific gapmer designs of this nature include F-G-F′ designs selectedfrom a group consisting of a gap with 14 nucleosides and independently 1to 4 modified nucleosides in the wings including 1-14-1, 1-14-2, 2-14-1,1-14-3, 3-14-1, 1-14-4, 4-14-1, 2-14-2, 2-14-3, 3-14-2 2-14-4, 4-14-2,3-14-3, 3-14-4 and 4-14-3 gapmers.

Specific gapmer designs of this nature include F-G-F′ designs selectedfrom a group consisting of a gap with 15 nucleosides and independently 1to 4 modified nucleosides in the wings including 1-15-1, 1-15-2, 2-15-1,1-15-3, 3-15-1, 1-15-4, 4-15-1, 2-15-2, 2-15-3, 3-15-2 2-15-4, 4-15-2,3-15-3, 3-15-4 and 4-15-3 gapmers.

Specific gapmer designs of this nature include F-G-F′ designs selectedfrom a group consisting of a gap with 16 nucleosides and independently 1to 4 modified nucleosides in the wings including 1-16-1, 1-16-2, 2-16-1,1-15-3, 3-16-1, 1-16-4, 4-16-1, 2-16-2, 2-16-3, 3-16-2 2-16-4, 4-16-2,3-16-3, 3-16-4 and 4-16-3 gapmers.

In some embodiments the F-G-F′ design is selected from 2-10-4, 3-10-3and 4-10-2.

In some embodiments the F-G-F′ design is selected from 2-11-4, 3-11-2,3-11-3 and 4-11-2.

In some embodiments the F-G-F′ design is selected from 2-12-2, 2-12-3,2-12-4, 3-12-2, 3-12-3, and 4-12-2.

In some embodiments the F-G-F′ design is selected from 2-13-2, 2-13-3,2-13-4, 3-13-3 and 4-13-2.

In some embodiments the F-G-F′ design is selected from 2-14-2, 2-14-4,3-14-3 and 4-14-2.

In some embodiments the F-G-F′ design is selected from 2-15-2 and2-16-2.

In some embodiments the F-G-F′ design is selected from the designsindicated in table 3.

In all instances the F-G-F′ design may further include region D and/orD′, which may have 1, 2 or 3 nucleoside units, such as DNA units.Preferably, the nucleosides in region F and F′ are modified nucleosides,while nucleotides in region G are preferably unmodified nucleosides.

In each design, the preferred modified nucleoside is LNA.

In another embodiment all the internucleoside linkages in the gap in agapmer are phosphorothioate and/or boranophosphate linkages. In anotherembodiment all the internucleoside linkages in the flanks (F and F′region) in a gapmer are phosphorothioate and/or boranophosphatelinkages. In another preferred embodiment all the internucleosidelinkages in the D and D′ region in a gapmer are phosphodiester linkages.

For specific gapmers as disclosed herein, when the cytosine (C) residuesare annotated as 5-methyl-cytosine, in various embodiments, one or moreof the C's present in the oligonucleotide may be unmodified C residues.

Further gapmer designs are disclosed in WO2004/046160, WO2007/146511 andincorporated by reference.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds in table 3.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds with CMP-ID-NO: 4_1to 150_2.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds with CMP-ID-NO: 4_1to 678_1.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds with CMP-ID-NO: 4_1to 818_1 (see oligonucleotide sequences listed in table 3 in theExamples section).

For certain embodiments of the invention, the oligonucleotide is anoligonucleotide compound with CMP-ID-NO: 155_1 or 165_1.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds with CMP-ID-NO:169_52, 169_50 or 169_56.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds with CMP-ID-NO:172_1, 272_1, 572_7, 572_6 or 572_5.

For certain embodiments of the invention, the oligonucleotide is anoligonucleotide compound with CMP-ID-NO: 175_1.

For certain embodiments of the invention, the oligonucleotide is anoligonucleotide compound with CMP-ID-NO: 178_1.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds with CMP-ID-NO:573_8, 186_1 or 187_1.

For certain embodiments of the invention, the oligonucleotide is anoligonucleotide compound with CMP-ID-NO: 186_1.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds with CMP-ID-NO:200_1, 204_1, 206_1, 35_2 or 209_1.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds with CMP-ID-NO:585_1, 585_8, 586_9, 586_5, 586_8, 586_4 or 586_6.

For certain embodiments of the invention, the oligonucleotide is anoligonucleotide compound with CMP-ID-NO: 233_1.

For certain embodiments of the invention, the oligonucleotide is anoligonucleotide compound with CMP-ID-NO: 237_8 or 590_13.

For certain embodiments of the invention, the oligonucleotide is anoligonucleotide compound with CMP-ID-NO: 220_1.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds with CMP-ID-NO:591_1, 592_2, 592_4 or 241_9.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds with CMP-ID-NO:597_4, 598_4, 39_1 or 602_1.

For certain embodiments of the invention, the oligonucleotide is anoligonucleotide compound with CMP-ID-NO: 39_1.

For certain embodiments of the invention, the oligonucleotide is anoligonucleotide compound with CMP-ID-NO: 611_7.

For certain embodiments of the invention, the oligonucleotide is anoligonucleotide compound with CMP-ID-NO: 271_1 or 278_1.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds with CMP-ID-NO:616_4, 621_2, 621_1, 622_3, 622_5, 622_4, 6243, 624_5, 287_1, 625_6,626_7, 626_8, 626_9, 48_1, 631_6, 631_1, 303_1, 304_6 or 304_10.

For certain embodiments of the invention, the oligonucleotide is anoligonucleotide compound with CMP-ID-NO: 636_8.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds with CMP-ID-NO:638_8, 639_5, 331_1 or 640_4.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds with CMP-ID-NO:359_1, 361_1, 361_5, 362_1 or 641_5.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds with CMP-ID-NO:378_1, 379_1, 399_1.

For certain embodiments of the invention, the oligonucleotide isselected from the group of oligonucleotide compounds with CMP-ID-NO:403_1, 405_1, 642_12, 642_13, 644_3 or 646_16.

For certain embodiments of the invention, the oligonucleotide is anoligonucleotide compound with CMP-ID-NO: 85_1 or 425_5.

For certain embodiments of the invention, the oligonucleotide is anoligonucleotide compound with CMP-ID-NO: 116_1.

For certain embodiments of the invention, the oligonucleotide is anoligonucleotide compound with CMP-ID-NO: 123_1 or 124_1.

For certain embodiments of the invention, the oligonucleotide is anoligonucleotide compound with CMP-ID-NO: 126_2.

Method of Manufacture

In a further aspect, the invention provides methods for manufacturingthe oligonucleotides of the invention comprising reacting nucleotideunits and thereby forming covalently linked contiguous nucleotide unitscomprised in the oligonucleotide. Preferably, the method usesphophoramidite chemistry (see for example Caruthers et al, 1987, Methodsin Enzymology vol. 154, pages 287-313). In a further embodiment themethod further comprises reacting the contiguous nucleotide sequencewith a conjugating moiety (ligand). In a further aspect a method isprovided for manufacturing the composition of the invention, comprisingmixing the oligonucleotide or conjugated oligonucleotide of theinvention with a pharmaceutically acceptable diluent, solvent, carrier,salt and/or adjuvant.

Pharmaceutical Composition

In a further aspect, the invention provides pharmaceutical compositionscomprising any of the aforementioned oligonucleotides and/oroligonucleotide conjugates and a pharmaceutically acceptable diluent,carrier, salt and/or adjuvant. A pharmaceutically acceptable diluentincludes phosphate-buffered saline (PBS) and pharmaceutically acceptablesalts include, but are not limited to, sodium and potassium salts.

WO 2007/031091 provides suitable and preferred examples ofpharmaceutically acceptable diluents, carriers and adjuvants (herebyincorporated by reference). Suitable dosages, formulations,administration routes, compositions, dosage forms, combinations withother therapeutic agents, pro-drug formulations are also provided inWO2007/031091.

Oligonucleotides or oligonucleotide conjugates of the invention may bemixed with pharmaceutically acceptable active or inert substances forthe preparation of pharmaceutical compositions or formulations.Compositions and methods for the formulation of pharmaceuticalcompositions are dependent upon a number of criteria, including, but notlimited to, route of administration, extent of disease, or dose to beadministered.

In some embodiments, the oligonucleotide or oligonucleotide conjugate ofthe invention is a prodrug. In particular with respect tooligonucleotide conjugates the conjugate moiety is cleaved of theoligonucleotide once the prodrug is delivered to the site of action,e.g. the target cell.

Applications

The oligonucleotides of the invention may be utilized as researchreagents for, for example, therapeutics and prophylaxis.

In research, such oligonucleotides may be used to specifically modulatethe synthesis of UBE3A protein in cells (e.g. in vitro cell cultures)and experimental animals thereby facilitating functional analysis of thetarget or an appraisal of its usefulness as a target for therapeuticintervention. The target modulation is achieved by degrading orinhibiting a modulator of the gene or mRNA producing the protein.

For therapeutics, an animal or a human, suspected of having a disease ordisorder, which can be treated by modulating the expression of UBE3A.

The invention provides methods for treating or preventing a disease,comprising administering a therapeutically or prophylactically effectiveamount of an oligonucleotide, an oligonucleotide conjugate or apharmaceutical composition of the invention to a subject suffering fromor susceptible to the disease.

The invention also relates to an oligonucleotide, a composition or aconjugate as defined herein for use as a medicament.

The oligonucleotide, oligonucleotide conjugate or a pharmaceuticalcomposition according to the invention is typically administered in aneffective amount.

The invention also provides for the use of the oligonucleotide oroligonucleotide conjugate of the invention as described for themanufacture of a medicament for the treatment of a disorder as referredto herein, or for a method of the treatment of as a disorder as referredto herein.

The disease or disorder, as referred to herein, is associated withexpression of UBE3A. In some embodiments the disease or disorder may beassociated with a mutation in the maternal UBE3A gene. In someembodiments, the target nucleic acid is a regulator of the paternalUBE3A gene.

The methods of the invention are preferably employed for treatment orprophylaxis against diseases caused by abnormal levels and/or activityof UBE3A. The disease may in particular be caused by reduced levelsand/or activity of UBE3A protein.

The invention further relates to use of an oligonucleotide,oligonucleotide conjugate or a pharmaceutical composition as definedherein for the manufacture of a medicament for the treatment of abnormallevels and/or activity of UBE3A, in particular low levels and/oractivity of UBE3A.

In one embodiment, the invention relates to oligonucleotides,oligonucleotide conjugates or pharmaceutical compositions for use in thetreatment of Angelman syndrome.

Administration

The oligonucleotides or pharmaceutical compositions of the presentinvention may be administered topical (such as, to the skin, inhalation,ophthalmic or otic) or enteral (such as, orally or through thegastrointestinal tract) or parenteral (such as, intravenous,subcutaneous, intra-muscular, intracerebral, intracerebroventricular orintrathecal).

In a preferred embodiment the oligonucleotide or pharmaceuticalcompositions of the present invention are administered by a parenteralroute including intravenous, intraarterial, subcutaneous,intraperitoneal or intramuscular injection or infusion, intrathecal orintracranial, e.g., intracerebral or intraventricular, administration.In one embodiment the active oligonucleotide or oligonucleotideconjugate is administered intracerebral or intracerebroventricular. Inanother embodiment the active oligonucleotide or oligonucleotideconjugate is administered intrathecal.

The invention also provides for the use of the oligonucleotide oroligonucleotide conjugate of the invention as described for themanufacture of a medicament wherein the medicament is in a dosage formfor intrathecal administration.

The invention also provides for the use of the oligonucleotide oroligonucleotide conjugate of the invention as described for themanufacture of a medicament wherein the medicament is in a dosage formfor intracerebral or intraventricular administration.

The invention also provides for the use of the oligonucleotide oroligonucleotide conjugate of the invention as described for themanufacture of a medicament wherein the medicament is in a dosage formfor intracerebroventricular administration.

Combination Therapies

In some embodiments the oligonucleotide, oligonucleotide conjugate orpharmaceutical composition of the invention is for use in a combinationtreatment with another therapeutic agent. The therapeutic agent can forexample be anticonvulsant medication.

EMBODIMENTS

The following embodiments of the present invention may be used incombination with any other embodiments described herein.

1. An antisense oligonucleotide which comprises or consists of acontiguous nucleotide sequence of 10 to 30 nucleotides in length capableof inducing human paternal UBE3A expression, in particular in a neuronalcell.

2. The oligonucleotide of embodiment 1, wherein the contiguousnucleotide sequence is at least 95% complementarity to the part of humanSNHG14 long non-coding RNA which is downstream of SNORD109Bcorresponding to position 25278410 to 25419462 on chromosome 15.

3. The oligonucleotide of embodiment 1 or 2, wherein the oligonucleotideis capable of hybridizing to a target nucleic acid of SEQ ID NO: 1 witha ΔG° below −10 kcal.

4. The oligonucleotide of embodiment 1-3, wherein the contiguousnucleotide sequence is at least 95%, such as 98%, such as 100%complementarity to region of the target nucleic acid of SEQ ID NO: 1and/or 2.

5. The oligonucleotide of embodiment 1-3, wherein the contiguousnucleotide sequence is 100% complementary to a region of the targetnucleic acid of position 1 to 55318 of SEQ ID NO: 1.

6. The oligonucleotide of embodiment 1-4, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid, wherein the subsequence is selected from the groupconsisting of the regions indicated in table 1 or 2.

7. The oligonucleotide of embodiment 1-4, wherein the contiguousnucleotide sequence is at least 98% complementarity to the part of humanSNHG14 long non-coding RNA which is antisense to the UBE3A pre-mRNA.

8. The oligonucleotide of embodiments 1-4 or 7, wherein theoligonucleotide is capable of hybridizing to a target nucleic acidcorresponding to position 55319 to 141053 of SEQ ID NO: 1, with a ΔG°below −10 kcal.

9. The oligonucleotide of embodiments 1-4 or 7-8, wherein the contiguousnucleotide sequence is 100% complementary to a target nucleic acid ofposition 55319 to 141053 of SEQ ID NO: 1.

10. The oligonucleotide of embodiment 1-8, wherein the target nucleicacid is RNA.

11. The oligonucleotide of embodiment 10, wherein the RNA is a longnon-coding RNA.

12. The oligonucleotide of embodiment 1-11, wherein the contiguousnucleotide sequence comprises or consists of at least 10 contiguousnucleotides, particularly 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, or 29 contiguous nucleotides.

13. The oligonucleotide of embodiment 1-12, wherein the contiguousnucleotide sequence comprises or consists of from 12 to 22 nucleotides.

14. The oligonucleotide of embodiment 13, wherein the contiguousnucleotide sequence comprises or consists of from 15-20 nucleotides.

15. The oligonucleotide of embodiment 1-14, wherein the oligonucleotidecomprises or consists of 10 to 35 nucleotides in length.

16. The oligonucleotide of embodiment 15, wherein the oligonucleotidecomprises or consists of 15 to 24 nucleotides in length.

17. The oligonucleotide of embodiment 15 or 17, wherein theoligonucleotide comprises or consists of 17 to 22 nucleotides in length.

18. The oligonucleotide of embodiment 1-17, wherein the oligonucleotideor contiguous nucleotide sequence is single stranded.

19. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid, selected from the group consisting of the regionsindicated in table 1 or 2.

20. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid selected from the group consisting of position 1589-10889,46089-53989 and 60789-62489 of SEQ ID NO: 1.

21. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid corresponding to positions 5218-5240 of SEQ ID NO: 1.

22. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid corresponding to positions 5782-5803 of SEQ ID NO: 1.

23. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid corresponding to positions 8113-8139 of SEQ ID NO: 1.

24. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid corresponding to positions: 9200-9250 of SEQ ID NO: 1.

25. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid corresponding to positions: 11505-11555 of SEQ ID NO: 1.

26. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid corresponding to positions 13223-13242 of SEQ ID NO: 1.

27. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid corresponding to positions 15100-15150 of SEQ ID NO: 1.

28. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid corresponding to positions 15113-15180 of SEQ ID NO: 1.

29. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid corresponding to positions 29635-29705 of SEQ ID NO: 1.

30. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid corresponding to positions 30590-30740 of SEQ ID NO: 1.

31. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid corresponding to positions 39800-39855 of SEQ ID NO: 1.

32. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid corresponding to positions 44435-44460 of SEQ ID NO: 1.

33. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid corresponding to positions 45245-45270 of SEQ ID NO: 1

34. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid to positions 46380-46430 of SEQ ID NO: 1.

35. The oligonucleotide of embodiment 1-18, wherein the contiguousnucleotide sequence is complementary to a sub-sequence of the targetnucleic acid corresponding to positions 68915-68940 of SEQ ID NO: 1.

36. The oligonucleotide of embodiment 1-35, wherein the oligonucleotideis neither siRNA nor self-complementary.

37. The oligonucleotide of embodiment 1-36, wherein the contiguousnucleotide sequence comprises or consists of a sequence selected fromthe group consisting of SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 1819, 20, 21, 22, 23, 23, 24, 25, 26, 26, 27, 28, 29, 30,31, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 44, 45, 45,46, 47, 48, 49, 50, 51, 52, 53, 53, 54, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 79, 80, 81, 8283, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95,95, 96, 96, 96, 97, 98, 99, 100, 101, 101, 102, 103, 104, 105, 106, 107,108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121,122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135,136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149,150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163,164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177,178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191,192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205,206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219,220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233,234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247,248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261,262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275,276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289,290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303,304, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316,317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330,331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344,345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358,359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372,373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386,387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400,401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414,415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428,429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442,443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456,457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470,471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484,485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498,499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512,513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526,527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540,541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554,555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568,569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582,583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596,596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609,610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623,624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637,638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651,652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665,666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679,680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693,694, 695, 696, 697, 698, 699, 700, 702, 703, 704, 705, 706, 707, 708,709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 719, 720, 721,722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735,736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749,750, 751, 752, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764,765, 766, 767, 768, 769, 770, 772, 773, 774, 775, 776, 777, 778, 779,780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793,794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807,808, 809, 810, 811, 812, 813, 814, 815, 816, 817 and 818.

38. The oligonucleotide of embodiment 1-36, wherein the contiguousnucleotide sequence comprises or consists of a sequence selected fromthe group consisting of SEQ ID NO: 166, 167, 167 or 169 (see motifsequences listed in table 3 in the Examples section).

39. The oligonucleotide of embodiment 1-36, wherein the contiguousnucleotide sequence comprises or consists of a sequence selected fromthe group consisting of SEQ ID NO: 570, 571, 572, 679, 680, 681, 682 and683 (see motif sequences listed in table 3 in the Examples section).

40. The oligonucleotide of embodiment 1-36, wherein the contiguousnucleotide sequence comprises or consists of a sequence selected fromthe group consisting of SEQ ID NO: 570, 571, 572, 679, 680, 681, 682 and683 (see motif sequences listed in table 3 in the Examples section).

41. The oligonucleotide of embodiment 1-36, wherein the contiguousnucleotide sequence comprises or consists of a sequence selected fromthe group consisting of SEQ ID NO: 35, 199 to 210 or SEQ ID NO: 582 to584 (see motif sequences listed in table 3 in the Examples section).

42. The oligonucleotide of embodiment 1-36, wherein the contiguousnucleotide sequence comprises or consists of a sequence selected fromthe group consisting of SEQ ID NO: 236, 237, 238, 239, 240 and 590 (seemotif sequences listed in table 3 in the Examples section).

43. The oligonucleotide of embodiment 1-36, wherein the contiguousnucleotide sequence comprises or consists of a sequence selected fromthe group consisting of SEQ ID NO: 221 to 225 or SEQ ID NO: 585 to 589(see motif sequences listed in table 3 in the Examples section).

44. The oligonucleotide of embodiment 1-36, wherein the contiguousnucleotide sequence comprises or consists of a sequence selected fromthe group consisting of SEQ ID NO: 241 or 591 (see motif sequenceslisted in table 3 in the Examples section).

45. The oligonucleotide of embodiment 1-36, wherein the contiguousnucleotide sequence comprises or consists of a sequence selected fromthe group consisting of SEQ ID NO: 46-48, 285 to 305 or SEQ ID NO: 613to 632 or SEQ ID NO: 721 to 807 (see motif sequences listed in table 3in the Examples section).

46. The oligonucleotide of embodiment 1-36, wherein the contiguousnucleotide sequence comprises or consists of a sequence selected fromthe group consisting of SEQ ID NO: 331, 332, 638, 639, 640, 808, 809,810, 811, 812, 813, 814 and 815 (see motif sequences listed in table 3in the Examples section).

47. The oligonucleotide of embodiment 1-36, wherein the contiguousnucleotide sequence comprises or consists of a sequence selected fromthe group consisting of SEQ ID NO: 409 to 411 or SEQ ID NO: 642 to 646or SEQ ID NO: 816 to 818 (see motif sequences listed in table 3 in theExamples section).

48. The oligonucleotide of embodiment 1-47, wherein the contiguousnucleotide sequence has zero to three mismatches compared to the targetnucleic acid it is complementary to.

49. The oligonucleotide of embodiment 48, wherein the contiguousnucleotide sequence has one mismatch compared to the target nucleicacid.

50. The oligonucleotide of embodiment 48, wherein the contiguousnucleotide sequence has two mismatches compared to the target nucleicacid.

51. The oligonucleotide of embodiment 48, wherein the contiguousnucleotide sequence is fully complementary to the target nucleic acidsequence.

52. The oligonucleotide of embodiment 1-51, comprising one or moremodified nucleosides.

53. The oligonucleotide of embodiment 52, wherein the one or moremodified nucleoside is a high-affinity modified nucleosides.

54. The oligonucleotide of embodiment 52 or 53, wherein the one or moremodified nucleoside is a 2′ sugar modified nucleoside.

55. The oligonucleotide of embodiment 54, wherein the one or more 2′sugar modified nucleoside is independently selected from the groupconsisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA,2′-O-methoxyethyl-RNA, 2′-amino-DNA, 2′-fluoro-DNA, 2′-fluoro-ANA andLNA nucleosides.

56. The oligonucleotide of embodiment 54, wherein the one or moremodified nucleoside is a LNA nucleoside.

57. The oligonucleotide of embodiment 56, wherein the modified LNAnucleoside is oxy-LNA.

58. The oligonucleotide of embodiment 57, wherein the modifiednucleoside is beta-D-oxy-LNA.

59. The oligonucleotide of embodiment 57, wherein the modifiednucleoside is alpha-L-oxy-LNA

60. The oligonucleotide of embodiment 56, wherein the modifiednucleoside is thio-LNA.

61. The oligonucleotide of embodiment 56, wherein the modifiednucleoside is amino-LNA.

62. The oligonucleotide of embodiment 56, wherein the modifiednucleoside is cET.

63. The oligonucleotide of embodiment 56, wherein the modifiednucleoside is ENA.

64. The oligonucleotide of embodiment 56, wherein the modified LNAnucleoside is selected from beta-D-oxy-LNA, alpha-L-oxy-LNA,beta-D-amino-LNA, alpha-L-amino-LNA, beta-D-thio-LNA, alpha-L-thio-LNA,(S)cET, (R)cET beta-D-ENA and alpha-L-ENA.

65. The oligonucleotide of any one of embodiments 1-64, wherein theoligonucleotide comprises at least one modified internucleoside linkage.

66. The oligonucleotide of embodiment 65, wherein the modifiedinternucleoside linkage is nuclease resistant.

67. The oligonucleotide of embodiment 65 or 66, wherein at least 50% ofthe internucleoside linkages within the contiguous nucleotide sequenceare phosphorothioate internucleoside linkages or boranophosphateinternucleoside linkages.

68. The oligonucleotide of embodiment 65 or 66, wherein all theinternucleoside linkages within the contiguous nucleotide sequence arephosphorothioate internucleoside linkages.

69. The oligonucleotide of embodiment 1-68, wherein the oligonucleotideis capable of recruiting RNase H.

70. The oligonucleotide of embodiment 69, wherein the oligonucleotide isa gapmer.

71. The oligonucleotide of embodiment 69 or 70, wherein theoligonucleotide is a gapmer of formula 5′-F-G-F′-3′, where region F andF′ independently comprise or consist of 1-7 modified nucleosides and Gis a region between 6 and 16 nucleosides which are capable of recruitingRNaseH.

72. The oligonucleotide of embodiment 71, wherein the modifiednucleoside is a 2′ sugar modified nucleoside independently selected fromthe group consisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA,2′-O-methoxyethyl-RNA, 2′-amino-DNA, 2′-fluoro-DNA, arabino nucleic acid(ANA), 2′-fluoro-ANA and LNA nucleosides.

73. The oligonucleotide of embodiment 71 or 72, wherein one or more ofthe modified nucleosides in region F and F′ is a LNA nucleoside.

74. The oligonucleotide of embodiment 73, wherein all the modifiednucleosides in region F and F′ are LNA nucleosides.

75. The oligonucleotide of embodiment 74, wherein region F and F′consist of LNA nucleosides.

76. The oligonucleotide of embodiment 73-75, wherein all the modifiednucleosides in region F and F′ are oxy-LNA nucleosides.

77. The oligonucleotide of embodiment 73, wherein at least one of regionF or F′ further comprises at least one 2′ substituted modifiednucleoside independently selected from the group consisting of2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA,2′-amino-DNA and 2′-fluoro-DNA.

78. The oligonucleotide of embodiment 73-77, wherein the RNaseHrecruiting nucleosides in region G are independently selected from DNA,alpha-L-LNA, C4′ alkylated DNA, ANA and 2′F-ANA and UNA.

79. The oligonucleotide of embodiment 78, wherein the nucleosides inregion G is DNA and/or alpha-L-LNA nucleosides.

80. The oligonucleotide of embodiment 78 or 79, wherein region Gconsists of at least 75% DNA nucleosides.

81. The oligonucleotide of embodiment 1-80, wherein the oligonucleotideis capable of increasing the expression of UBE3A by at least 30%compared to a control.

82. The oligonucleotide of embodiment 1-81, wherein the level of theSNHG14 transcript downstream of SNORD109B is reduced by at least 20%compared to a control.

83. The oligonucleotide of embodiment 1-82, wherein the expression ofSNORD115 is not significantly affected compared to a control.

84. The oligonucleotide of embodiment 1-83, wherein the oligonucleotideis selected from CMP ID NO: 4_1 to 678_1.

85. The oligonucleotide of embodiment 1-83, wherein the oligonucleotideis selected from the group consisting of CMP ID NO: 4_1, 4_2, 5_1, 5_2,6_1, 6_2, 7_1, 7_2, 8_1, 9_1, 10_1, 11_1, 11_2, 12_1, 12_2, 13_1, 13_2,14_1, 15_1, 16_1, 17_1, 17_2, 18_1, 18_2, 19_1, 19_2, 20_1, 21_1, 22_1,23_1, 23_2, 24_1, 25_1, 26_1, 26_2, 27_1, 28_1, 28_2, 29_1, 29_2, 30_1,31_1, 31_2, 32_1, 33_1, 34_1, 34_2, 34_3, 34_4, 34_5, 34_6, 34_7, 35_1,35_2, 36_1, 37_1, 38_1, 38_2, 38_3, 38_4, 38_5, 38_6, 39_1, 39_2, 39_3,39_4, 39_5, 40_1, 40_2, 40_3, 40_4, 40_5, 40_6, 40_7, 40_8, 41_1, 42_1,43_1, 44_1, 44_2, 45_1, 45_2, 46_1, 47_1, 48_1, 48_2, 48_3, 48_4, 48_5,48_6, 48_7, 49_1, 50_1, 51_1, 52_1, 53_1, 53_2, 54_1, 54_2, 54_3, 55_1,55_2, 56_1, 57_1, 58_1, 58_2, 58_3, 59_1, 59_2, 60_1, 60_2, 60_3, 61_1,62_1, 63_1, 64_1, 64_2, 65_1, 66_1, 67_1, 68_1, 69_1, 69_2, 69_3, 70_1,70_2, 70_3, 71_1, 72_1, 72_2, 73_1, 73_2, 73_3, 74_1, 74_2, 75_1, 75_2,76_1, 77_1, 77_2, 77_3, 78_1, 79_1, 79_2, 79_3, 80_1, 80_2, 80_3, 81_1,82_1, 82_2, 83_1, 83_2, 84_1, 84_2, 85_1, 85_2, 86_1, 87_1, 88_1, 88_2,89_1, 90_1, 91_1, 92_1, 93_1, 94_1, 95_1, 95_2, 96_1, 96_2, 96_3, 97_1,97_2, 97_3, 97_4, 98_1, 98_2, 98_3, 99_1, 99_2, 99_3, 99_4, 100_1,100_2, 100_3, 101_1, 101_2, 101_3, 101_4, 102_1, 102_2, 102_3, 102_4,103_1, 103_2, 103_3, 103_4, 104_1, 104_2, 104_3, 105_1, 105_2, 105_3,105_4, 106_1, 106_2, 106_3, 106_4, 107_1, 107_2, 107_3, 107_4, 108_1,108_2, 108_3, 108_4, 109_1, 109_2, 109_3, 109_4, 110_1, 110_2, 111_1,111_2, 111_3, 112_1, 112_2, 113_1, 114_1, 115_1, 116_1, 117_1, 118_1,119_1, 120_1, 120_2, 121_1, 122_1, 123_1, 124_1, 125_1, 126_1, 126_2,127_1, 128_1, 128_2, 128_3, 128_4, 129_1, 129_2, 130_1, 131_1, 132_1,132_2, 132_3, 133_1, 133_2, 133_3, 133_4, 134_1, 134_2, 135_1, 135_2,136_1, 137_1, 138_1, 139_1, 140_1, 141_1, 142_1, 143_1, 144_1, 145_1,145_2, 146_1, 146_2, 147_1, 148_1, 149_1, 150_1, 150_2, 151_1, 152_1,153_1, 154_1, 155_1, 156_1, 157_1, 158_1, 159_1, 160_1, 161_1, 162_1,163_1, 164_1, 165_1, 166_1, 167_1, 168_1, 169_1, 169_10, 169_11, 169_12,169_13, 169_14, 169_15, 169_16, 169_17, 169_18, 169_19, 169_2, 169_20,169_21, 169_22, 169_23, 169_24, 169_25, 169_26, 169_27, 169_28, 169_29,169_3, 169_30, 169_31, 169_32, 169_33, 169_34, 169_35, 169_36, 169_37,169_38, 169_39, 169_4, 169_40, 169_41, 169_42, 169_43, 169_44, 169_45,169_46, 169_47, 169_48, 169_49, 169_5, 169_50, 169_51, 169_52, 169_53,169_54, 169_55, 169_56, 169_57, 169_6, 169_7, 169_8, 169_9, 169_58,169_59, 169_60, 169_61, 169_62, 170_1, 171_1, 172_1, 173_1, 174_1,175_1, 176_1, 177_1, 178_1, 179_1, 180_1, 181_1, 182_1, 183_1, 184_1,185_1, 186_1, 187_1, 188_1, 189_1, 190_1, 191_1, 192_1, 193_1, 194_1,195_1, 196_1, 197_1, 198_1, 199_1, 200_1, 201_1, 202_1, 203_1, 204_1,205_1, 206_1, 207_1, 208_1, 208_2, 208_3, 208_4, 208_5, 208_6, 208_7,209_1, 209_10, 209_2, 209_3, 209_4, 209_5, 209_6, 209_7, 209_8, 209_9,210_1, 211_1, 212_1, 213_1, 214_1, 215_1, 216_1, 217_1, 218_1, 219_1,220_1, 221_1, 222_1, 223_1, 224_1, 225_1, 226_1, 227_1, 228_1, 229_1,230_1, 231_1, 232_1, 233_1, 234_1, 235_1, 236_1, 236_10, 236_11, 236_12,236_13, 236_14, 236_15, 236_16, 236_2, 236_3, 236_4, 236_5, 236_6,236_7, 236_8, 236_9, 236_17, 236_18, 236_19, 236_20, 236_21, 237_1,237_10, 237_11, 237_12, 237_13, 237_14, 237_15, 237_16, 237_2, 237_3,237_4, 237_5, 237_6, 237_7, 237_8, 237_9, 237_17, 237_18, 237_19,237_20, 237_21, 238_1, 239_1, 239_10, 239_11, 239_12, 239_13, 239_14,239_15, 239_16, 239_2, 239_3, 239_4, 239_5, 239_6, 239_7, 239_8, 239_9,239_17, 239_18, 239_19, 239_20, 239_21, 240_1, 241_1, 241_10, 241_2,241_3, 241_4, 241_5, 241_6, 241_7, 241_8, 241_9, 241_11, 241_12, 241_13,241_14, 241_15, 242_1, 243_1, 244_1, 244_2, 244_3, 244_4, 244_5, 245_1,246_1, 247_1, 248_1, 249_1, 250_1, 251_1, 252_1, 253_1, 254_1, 255_1,256_1, 257_1, 258_1, 259_1, 260_1, 261_1, 262_1, 263_1, 264_1, 265_1,266_1, 267_1, 268_1, 269_1, 270_1, 271_1, 272_1, 273_1, 274_1, 275_1,276_1, 277_1, 278_1, 279_1, 280_1, 281_1, 282_1, 283_1, 284_1, 285_1,285_2, 285_3, 285_4, 285_5, 285_6, 285_7, 285_8, 285_9, 285_10, 285_11,286_1, 287_1, 288_1, 289_1, 290_1, 291_1, 292_1, 293_1, 294_1, 295_1,296_1, 297_1, 298_1, 299_1, 300_1, 301_1, 302_1, 303_1, 304_1, 304_10,304_2, 304_3, 304_4, 304_5, 304_6, 304_7, 304_8, 304_9, 304_11, 304_12,304_13, 304_14, 304_15, 305_1, 306_1, 307_1, 308_1, 309_1, 310_1, 311_1,312_1, 313_1, 314_1, 315_1, 316_1, 317_1, 318_1, 319_1, 320_1, 321_1,322_1, 323_1, 324_1, 325_1, 326_1, 327_1, 328_1, 329_1, 330_1, 331_1,332_1, 333_1, 334_1, 335_1, 336_1, 337_1, 338_1, 339_1, 340_1, 341_1,342_1, 343_1, 344_1, 345_1, 346_1, 347_1, 348_1, 349_1, 350_1, 351_1,352_1, 353_1, 354_1, 355_1, 356_1, 357_1, 358_1, 359_1, 360_1, 361_1,361_10, 361_2, 361_3, 361_4, 361_5, 361_6, 361_7, 361_8, 361_9, 362_1,362_10, 362_2, 362_3, 362_4, 362_5, 362_6, 362_7, 362_8, 362_9, 363_1,364_1, 365_1, 366_1, 367_1, 368_1, 369_1, 370_1, 371_1, 372_1, 373_1,374_1, 375_1, 376_1, 377_1, 378_1, 379_1, 380_1, 381_1, 382_1, 383_1,384_1, 385_1, 386_1, 387_1, 388_1, 389_1, 390_1, 391_1, 392_1, 393_1,394_1, 395_1, 396_1, 397_1, 398_1, 399_1, 400_1, 401_1, 402_1, 403_1,404_1, 405_1, 406_1, 407_1, 408_1, 409_1, 410_1, 411_1, 412_1, 413_1,414_1, 415_1, 416_1, 417_1, 418_1, 419_1, 420_1, 421_1, 422_1, 423_1,424_1, 425_1, 425_10, 425_2, 425_3, 425_4, 425_5, 425_6, 425_7, 425_8,425_9, 426_1, 427_1, 428_1, 429_1, 430_1, 431_1, 432_1, 433_1, 434_1,435_1, 436_1, 437_1, 438_1, 439_1, 440_1, 441_1, 442_1, 443_1, 444_1,445_1, 446_1, 447_1, 448_1, 449_1, 450_1, 451_1, 452_1, 453_1, 454_1,455_1, 456_1, 457_1, 458_1, 459_1, 460_1, 461_1, 462_1, 463_1, 464_1,465_1, 466_1, 467_1, 468_1, 469_1, 470_1, 471_1, 472_1, 473_1, 474_1,475_1, 476_1, 477_1, 478_1, 479_1, 480_1, 481_1, 482_1, 483_1, 484_1,485_1, 486_1, 487_1, 488_1, 489_1, 490_1, 491_1, 492_1, 493_1, 494_1,495_1, 496_1, 497_1, 498_1, 499_1, 500_1, 501_1, 502_1, 503_1, 504_1,505_1, 506_1, 507_1, 508_1, 509_1, 510_1, 511_1, 512_1, 513_1, 514_1,515_1, 516_1, 517_1, 518_1, 519_1, 520_1, 521_1, 522_1, 523_1, 524_1,525_1, 526_1, 527_1, 528_1, 529_1, 530_1, 531_1, 532_1, 533_1, 534_1,535_1, 536_1, 537_1, 538_1, 539_1, 540_1, 541_1, 542_1, 543_1, 544_1,545_1, 546_1, 547_1, 548_1, 549_1, 550_1, 551_1, 552_1, 553_1, 554_1,555_1, 556_1, 557_1, 558_1, 559_1, 560_1, 561_1, 562_1, 563_1, 564_1,565_1, 566_1, 567_1, 568_1, 569_1, 570_1, 570_2, 570_3, 570_4, 570_5,570_6, 570_7, 570_8, 570_9, 570_10, 570_11, 570_12, 570_13, 570_14,571_1, 571_2, 571_3, 571_4, 571_5, 571_6, 571_7, 571_8, 571_9, 571_10,571_11, 571_12, 571_13, 571_14, 572_1, 572_2, 572_3, 572_4, 572_5,572_6, 572_7, 572_8, 572_9, 572_10, 572_11, 572_12, 572_13, 572_14,573_1, 573_2, 573_3, 573_4, 573_5, 573_6, 573_7, 573_8, 573_9, 573_10,573_11, 573_12, 573_13, 573_14, 574_1, 574_2, 574_3, 574_4, 574_5,574_6, 574_7, 574_8, 574_9, 574_10, 574_11, 574_12, 574_13, 574_14,575_1, 575_2, 575_3, 575_4, 575_5, 575_6, 575_7, 575_8, 575_9, 575_10,575_11, 575_12, 575_13, 575_14, 576_1, 576_2, 576_3, 576_4, 576_5,576_6, 576_7, 576_8, 576_9, 576_10, 576_11, 576_12, 576_13, 576_14,577_1, 577_2, 577_3, 577_4, 577_5, 577_6, 577_7, 577_8, 577_9, 577_10,577_11, 577_12, 577_13, 577_14, 578_1, 578_2, 578_3, 578_4, 578_5,578_6, 578_7, 578_8, 578_9, 579_1, 579_2, 579_3, 579_4, 579_5, 579_6,579_7, 579_8, 579_9, 580_1, 580_2, 580_3, 580_4, 580_5, 580_6, 580_7,580_8, 580_9, 581_1, 581_2, 581_3, 581_4, 581_5, 581_6, 581_7, 581_8,581_9, 582_1, 582_2, 582_3, 582_4, 582_5, 582_6, 582_7, 582_8, 582_9,583_1, 583_2, 583_3, 583_4, 583_5, 583_6, 583_7, 583_8, 583_9, 584_1,584_2, 584_3, 584_4, 584_5, 584_6, 584_7, 584_8, 585_1, 585_2, 585_3,585_4, 585_5, 585_6, 585_7, 585_8, 585_9, 585_10, 585_11, 585_12,585_13, 585_14, 586_1, 586_2, 586_3, 586_4, 586_5, 586_6, 586_7, 586_8,586_9, 586_10, 586_11, 586_12, 586_13, 586_14, 587_1, 587_2, 587_3,587_4, 587_5, 587_6, 587_7, 587_8, 587_9, 587_10, 587_11, 587_12,587_13, 587_14, 588_1, 588_2, 588_3, 588_4, 588_5, 588_6, 588_7, 588_8,588_9, 588_10, 588_11, 588_12, 588_13, 588_14, 589_1, 589_2, 589_3,589_4, 589_5, 589_6, 589_7, 589_8, 589_9, 589_10, 589_11, 589_12,589_13, 589_14, 590_1, 590_10, 590_11, 590_12, 590_13, 590_14, 590_15,590_2, 590_3, 590_4, 590_5, 590_6, 590_7, 590_8, 590_9, 590_16, 590_17,590_18, 590_19, 590_20, 591_1, 591_2, 592_1, 592_2, 592_3, 592_4, 592_5,592_6, 592_7, 592_8, 592_9, 592_10, 592_11, 592_12, 592_13, 592_14,593_1, 593_2, 593_3, 593_4, 594_1, 594_2, 594_3, 594_4, 595_1, 595_2,595_3, 595_4, 596_1, 596_2, 596_3, 596_4, 597_1, 597_2, 597_3, 597_4,598_1, 598_2, 598_3, 598_4, 599_1, 599_2, 599_3, 599_4, 600_1, 600_2,600_3, 600_4, 601_1, 601_2, 601_3, 601_4, 602_1, 602_2, 602_3, 602_4,603_1, 603_2, 603_3, 603_4, 604_1, 604_2, 604_3, 604_4, 605_1, 605_2,605_3, 605_4, 606_1, 606_2, 606_3, 606_4, 607_1, 607_2, 607_3, 607_4,608_1, 608_2, 608_3, 608_4, 608_5, 608_6, 608_7, 608_8, 608_9, 609_1,609_2, 609_3, 609_4, 609_5, 609_6, 609_7, 609_8, 609_9, 610_1, 610_2,610_3, 610_4, 610_5, 610_6, 610_7, 610_8, 610_9, 611_1, 611_2, 611_3,611_4, 611_5, 611_6, 611_7, 611_8, 611_9, 612_1, 612_2, 612_3, 612_4,612_5, 612_6, 612_7, 612_8, 612_9, 613_1, 613_2, 613_3, 613_4, 613_5,613_6, 613_7, 613_8, 613_9, 613_10, 614_1, 614_2, 614_3, 614_4, 614_5,614_6, 614_7, 614_8, 614_9, 614_10, 615_1, 615_2, 615_3, 615_4, 615_5,615_6, 615_7, 615_8, 615_9, 615_10, 616_1, 616_2, 616_3, 616_4, 616_5,616_6, 616_7, 616_8, 616_9, 616_10, 617_1, 617_2, 617_3, 617_4, 617_5,617_6, 617_7, 617_8, 617_9, 617_10, 618_1, 618_2, 618_3, 618_4, 618_5,618_6, 618_7, 618_8, 618_9, 618_10, 619_1, 619_2, 619_3, 619_4, 619_5,619_6, 619_7, 619_8, 619_9, 619_10, 620_1, 620_2, 620_3, 620_4, 620_5,620_6, 620_7, 620_8, 620_9, 620_10, 621_1, 621_2, 621_3, 621_4, 621_5,621_6, 621_7, 621_8, 621_9, 621_10, 621_11, 622_1, 622_2, 622_3, 622_4,622_5, 622_6, 622_7, 622_8, 622_9, 622_10, 623_1, 623_2, 623_3, 623_4,623_5, 623_6, 623_7, 623_8, 623_9, 623_10, 624_1, 624_2, 624_3, 624_4,624_5, 624_6, 624_7, 624_8, 624_9, 624_10, 625_1, 625_2, 625_3, 625_4,625_5, 625_6, 625_7, 625_8, 625_9, 625_10, 625_11, 625_12, 625_13,625_14, 626_1, 626_2, 626_3, 626_4, 626_5, 626_6, 626_7, 626_8, 626_9,626_10, 626_11, 626_12, 626_13, 626_14, 627_1, 627_2, 627_3, 627_4,627_5, 627_6, 627_7, 627_8, 627_9, 627_10, 627_11, 627_12, 627_13,627_14, 628_1, 628_2, 628_3, 628_4, 628_5, 628_6, 628_7, 628_8, 628_9,628_10, 628_11, 628_12, 628_13, 628_14, 629_1, 629_10, 629_11, 629_2,629_3, 629_4, 629_5, 629_6, 629_7, 629_8, 629_9, 629_12, 629_13, 629_14,629_15, 629_16, 630_1, 630_2, 630_3, 631_1, 631_10, 631_2, 631_3, 631_4,631_5, 631_6, 631_7, 631_8, 631_9, 631_11, 631_12, 631_13, 631_14,631_15, 632_1, 632_2, 632_3, 632_4, 632_5, 632_6, 632_7, 632_8, 632_9,632_10, 632_11, 632_12, 632_13, 632_14, 633_1, 633_2, 633_3, 633_4,633_5, 633_6, 633_7, 633_8, 633_9, 634_1, 634_2, 634_3, 634_4, 634_5,634_6, 634_7, 634_8, 634_9, 635_1, 635_2, 635_3, 635_4, 635_5, 635_6,635_7, 635_8, 635_9, 636_1, 636_2, 636_3, 636_4, 636_5, 636_6, 636_7,636_8, 636_9, 637_1, 637_2, 637_3, 637_4, 637_5, 637_6, 637_7, 637_8,637_9, 638_1, 638_2, 638_3, 638_4, 638_5, 638_6, 638_7, 638_8, 638_9,638_10, 638_11, 638_12, 638_13, 638_14, 639_1, 639_2, 639_3, 639_4,639_5, 639_6, 639_7, 639_8, 639_9, 639_10, 639_11, 639_12, 639_13,639_14, 640_1, 640_2, 640_3, 640_4, 640_5, 640_6, 640_7, 640_8, 640_9,640_10, 640_11, 640_12, 640_13, 640_14, 641_1, 641_2, 641_3, 641_4,641_5, 641_6, 641_7, 641_8, 641_9, 642_1, 642_10, 642_11, 642_12,642_13, 642_14, 642_15, 642_16, 642_17, 642_2, 642_3, 642_4, 642_5,642_6, 642_7, 642_8, 642_9, 642_18, 642_19, 642_20, 642_21, 642_22,643_1, 644_1, 644_2, 644_3, 644_4, 644_5, 644_6, 645_1, 645_2, 645_3,645_4, 645_5, 645_6, 645_7, 645_8, 645_9, 645_10, 646_1, 646_10, 646_11,646_12, 646_13, 646_14, 646_15, 646_16, 646_17, 646_18, 646_19, 646_2,646_3, 646_4, 646_5, 646_6, 646_7, 646_8, 646_9, 646_20, 646_21, 646_22,646_23, 646_24, 647_1, 648_1, 649_1, 650_1, 651_1, 652_1, 653_1, 654_1,655_1, 656_1, 657_1, 658_1, 659_1, 660_1, 661_1, 662_1, 663_1, 664_1,665_1, 666_1, 667_1, 668_1, 669_1, 670_1, 671_1, 672_1, 673_1, 674_1,675_1, 676_1, 677_1, 678_1, 679_1, 679_2, 679_3, 679_4, 679_5, 680_1,680_2, 680_3, 680_4, 680_5, 681_1, 681_2, 681_3, 681_4, 681_5, 682_1,682_2, 682_3, 682_4, 682_5, 683_1, 683_2, 683_3, 683_4, 683_5, 684_1,684_2, 684_3, 684_4, 684_5, 685_1, 685_2, 685_3, 685_4, 685_5, 686_1,686_2, 686_3, 686_4, 686_5, 687_1, 687_2, 687_3, 687_4, 687_5, 688_1,688_2, 688_3, 688_4, 688_5, 689_1, 689_2, 689_3, 689_4, 689_5, 690_1,690_2, 690_3, 690_4, 690_5, 691_1, 691_2, 692_1, 692_2, 692_3, 692_4,692_5, 693_1, 693_2, 693_3, 693_4, 693_5, 694_1, 694_2, 694_3, 694_4,694_5, 695_1, 695_2, 695_3, 695_4, 695_5, 696_1, 696_2, 696_3, 696_4,696_5, 697_1, 697_2, 697_3, 697_4, 697_5, 698_1, 698_2, 698_3, 698_4,698_5, 699_1, 699_2, 699_3, 699_4, 699_5, 700_1, 700_2, 700_3, 700_4,700_5, 701_1, 701_2, 701_3, 701_4, 701_5, 702_1, 702_2, 702_3, 702_4,702_5, 703_1, 703_2, 703_3, 703_4, 703_5, 704_1, 704_2, 704_3, 704_4,704_5, 705_1, 705_2, 705_3, 705_4, 705_5, 706_1, 706_2, 706_3, 706_4,706_5, 707_1, 707_2, 707_3, 707_4, 707_5, 708_1, 708_2, 708_3, 708_4,708_5, 709_1, 709_2, 709_3, 709_4, 709_5, 710_1, 710_2, 710_3, 710_4,710_5, 711_1, 711_2, 711_3, 711_4, 711_5, 712_1, 712_2, 712_3, 712_4,712_5, 713_1, 713_2, 713_3, 713_4, 713_5, 714_1, 714_2, 714_3, 714_4,714_5, 715_1, 715_2, 715_3, 715_4, 715_5, 716_1, 716_2, 716_3, 716_4,716_5, 717_1, 717_2, 717_3, 717_4, 717_5, 718_1, 718_2, 719_1, 719_2,719_3, 719_4, 719_5, 720_1, 720_2, 720_3, 720_4, 720_5, 721_1, 721_2,721_3, 721_4, 721_5, 722_1, 722_2, 722_3, 722_4, 722_5, 723_1, 723_2,723_3, 723_4, 723_5, 724_1, 724_2, 724_3, 724_4, 724_5, 725_1, 725_2,725_3, 725_4, 725_5, 726_1, 726_2, 726_3, 726_4, 726_5, 727_1, 727_2,727_3, 727_4, 727_5, 728_1, 728_2, 728_3, 728_4, 728_5, 729_1, 729_2,729_3, 729_4, 729_5, 730_1, 730_2, 730_3, 730_4, 730_5, 731_1, 731_2,731_3, 731_4, 731_5, 732_1, 732_2, 732_3, 732_4, 732_5, 733_1, 733_2,733_3, 733_4, 733_5, 734_1, 734_2, 734_3, 734_4, 734_5, 735_1, 735_2,735_3, 735_4, 735_5, 736_1, 736_2, 736_3, 736_4, 736_5, 737_1, 737_2,737_3, 737_4, 737_5, 738_1, 738_2, 738_3, 738_4, 738_5, 738_6, 739_1,739_2, 739_3, 739_4, 739_5, 740_1, 740_2, 740_3, 740_4, 740_5, 741_1,741_2, 741_3, 741_4, 741_5, 742_1, 742_2, 742_3, 743_1, 743_2, 743_3,743_4, 743_5, 744_1, 744_2, 744_3, 744_4, 744_5, 745_1, 745_2, 745_3,745_4, 745_5, 746_1, 746_2, 746_3, 747_1, 747_2, 747_3, 747_4, 747_5,748_1, 748_2, 748_3, 748_4, 748_5, 749_1, 749_2, 749_3, 749_4, 749_5,750_1, 750_2, 750_3, 750_4, 751_1, 751_2, 751_3, 751_4, 751_5, 752_1,752_2, 752_3, 752_4, 752_5, 753_1, 753_2, 753_3, 753_4, 753_5, 754_1,754_2, 754_3, 754_4, 754_5, 755_1, 755_2, 755_3, 755_4, 755_5, 756_1,756_2, 756_3, 756_4, 756_5, 757_1, 757_2, 757_3, 757_4, 757_5, 758_1,758_2, 758_3, 758_4, 758_5, 759_1, 759_2, 759_3, 759_4, 759_5, 760_1,760_2, 760_3, 760_4, 760_5, 761_1, 761_2, 761_3, 761_4, 761_5, 762_1,762_2, 762_3, 762_4, 762_5, 763_1, 763_2, 763_3, 763_4, 763_5, 764_1,764_2, 764_3, 764_4, 764_5, 765_1, 765_2, 765_3, 765_4, 765_5, 766_1,766_2, 766_3, 766_4, 766_5, 767_1, 767_2, 767_3, 767_4, 767_5, 768_1,768_2, 768_3, 768_4, 768_5, 769_1, 769_2, 769_3, 769_4, 769_5, 770_1,770_2, 770_3, 770_4, 770_5, 771_1, 771_2, 771_3, 771_4, 771_5, 772_1,772_2, 772_3, 772_4, 772_5, 773_1, 773_2, 773_3, 773_4, 773_5, 774_1,774_2, 774_3, 774_4, 774_5, 775_1, 775_2, 775_3, 775_4, 775_5, 776_1,776_2, 776_3, 776_4, 776_5, 777_1, 777_2, 777_3, 777_4, 777_5, 778_1,778_2, 778_3, 778_4, 778_5, 779_1, 779_2, 779_3, 779_4, 779_5, 780_1,780_2, 780_3, 780_4, 780_5, 781_1, 782_1, 782_2, 782_3, 782_4, 782_5,783_1, 783_2, 783_3, 783_4, 783_5, 784_1, 784_2, 784_3, 784_4, 784_5,785_1, 786_1, 786_2, 786_3, 786_4, 786_5, 787_1, 787_2, 787_3, 787_4,787_5, 788_1, 788_2, 788_3, 788_4, 788_5, 789_1, 789_2, 789_3, 789_4,789_5, 790_1, 790_2, 790_3, 790_4, 790_5, 791_1, 791_2, 791_3, 791_4,791_5, 792_1, 792_2, 792_3, 792_4, 792_5, 793_1, 793_2, 793_3, 793_4,793_5, 794_1, 794_2, 794_3, 794_4, 794_5, 795_1, 795_2, 795_3, 795_4,795_5, 796_1, 796_2, 796_3, 796_4, 796_5, 797_1, 797_2, 797_3, 797_4,797_5, 798_1, 798_2, 798_3, 798_4, 798_5, 799_1, 799_2, 799_3, 799_4,799_5, 800_1, 800_2, 800_3, 800_4, 800_5, 801_1, 801_2, 801_3, 801_4,801_5, 802_1, 802_2, 802_3, 802_4, 802_5, 803_1, 803_2, 803_3, 803_4,803_5, 804_1, 804_2, 804_3, 804_4, 804_5, 805_1, 805_2, 805_3, 805_4,805_5, 806_1, 806_2, 806_3, 806_4, 806_5, 807_1, 807_2, 807_3, 807_4,807_5, 808_1, 808_2, 808_3, 808_4, 808_5, 809_1, 809_2, 809_3, 809_4,809_5, 810_1, 810_2, 810_3, 810_4, 810_5, 811_1, 811_2, 811_3, 811_4,811_5, 812_1, 812_2, 812_3, 812_4, 812_5, 813_1, 813_2, 813_3, 813_4,813_5, 814_1, 814_2, 814_3, 814_4, 814_5, 815_1, 815_2, 815_3, 815_4,815_5, 816_1, 816_2, 816_3, 816_4, 816_5, 816_6, 817_1 and 818_1.

86. The oligonucleotide of embodiment 85, wherein the oligonucleotide isselected from CMP-ID-NO: 155_1 or 165_1.

87. The oligonucleotide of embodiment 85, wherein the oligonucleotide isselected from the group consisting of CMP-ID-NO 169_52, 169_50 or169_56.

88. The oligonucleotide of embodiment 85, wherein the oligonucleotide isselected from the group consisting of CMP-ID-NO: 172_1, 272_1, 572_7,572_6 or 572_5.

89. The oligonucleotide of embodiment 85, wherein the oligonucleotide isselected from CMP-ID-NO: 175_1.

90. The oligonucleotide of embodiment 85, wherein the oligonucleotide isselected from CMP-ID-NO: 178_1.

91. The oligonucleotide of embodiment 85, wherein the oligonucleotide isselected from CMP-ID-NO: 573_8, 186_1 or 187_1.

92. The oligonucleotide of embodiment 85, wherein the oligonucleotide isselected from CMP-ID-NO: 186_1.

93. The oligonucleotide of embodiment 85, wherein the oligonucleotide isselected from the group consisting of CMP-ID-NO: 200_1, 204_1, 206_1,35_2 or 209_1.

94. The oligonucleotide of embodiment 85, wherein the oligonucleotide isselected from the group consisting of CMP-ID-NO: 585_1, 585_8, 586_9,586_5, 586_8, 586_4 or 586_6.

95. The oligonucleotide of embodiment 85, wherein the oligonucleotide isselected from CMP-ID-NO: 233_1.

96. The oligonucleotide of embodiment 85, wherein the oligonucleotide isselected from CMP-ID-NO: 237_8 or 590_13.

97. The oligonucleotide of embodiment 85, wherein the oligonucleotide isselected from CMP-ID-NO: 220_1.

98. The oligonucleotide of embodiment 85, wherein the oligonucleotide isselected from the group consisting of CMP-ID-NO: 591_1, 592_2, 592_4 or241_9.

99. The oligonucleotide of embodiment 85, wherein the oligonucleotide isselected from the group consisting of CMP-ID-NO: 597_4, 598_4, 39_1 or602_1.

100. The oligonucleotide of embodiment 85, wherein the oligonucleotideis selected from CMP-ID-NO: 39_1.

101. The oligonucleotide of embodiment 85, wherein the oligonucleotideis selected from CMP-ID-NO: 611_7.

102. The oligonucleotide of embodiment 85, wherein the oligonucleotideis selected from the group consisting of CMP-ID-NO: 271_1 or 278_1.

103. The oligonucleotide of embodiment 85, wherein the oligonucleotideis selected from the group consisting of CMP-ID-NO: 616_4, 621_2, 621_1,622_3, 622_5, 622_4, 624_3, 624_5, 287_1, 625_6, 626_7, 626_8, 626_9,48_1, 631_6, 631_1, 303_1, 304_6 or 304_10.

104. The oligonucleotide of embodiment 85, wherein the oligonucleotideis selected from CMP-ID-NO: 636_8.

105. The oligonucleotide of embodiment 85, wherein the oligonucleotideis selected from the group consisting of CMP-ID-NO: 638_8, 639_5, 331_1or 640_4.

106. The oligonucleotide of embodiment 85, wherein the oligonucleotideis selected from the group consisting of CMP-ID-NO: 359_1, 361_1, 361_5,362_1 or 641_5.

107. The oligonucleotide of embodiment 85, wherein the oligonucleotideis selected from the group consisting of CMP-ID-NO: 378_1, 379_1 or399_1.

108. The oligonucleotide of embodiment 85, wherein the oligonucleotideis selected from the group consisting of CMP-ID-NO: 403_1, 405_1,642_12, 642_13, 644_3 or 646_16.

109. The oligonucleotide of embodiment 85, wherein the oligonucleotideis selected from CMP-ID-NO: 85_1 or 425_5.

110. The oligonucleotide of embodiment 85, wherein the oligonucleotideis selected from CMP-ID-NO: 116_1.

111. The oligonucleotide of embodiment 85, wherein the oligonucleotideis selected from CMP-ID-NO: 123_1 or 124_1.

112. The oligonucleotide of embodiment 85, wherein the oligonucleotideis selected from CMP-ID-NO: 126_2.

113. A conjugate comprising the oligonucleotide according to any one ofembodiments 1-112, and at least one conjugate moiety covalently attachedto said oligonucleotide.

114. The oligonucleotide conjugate of embodiment 113, wherein theconjugate moiety is selected from carbohydrates, cell surface receptorligands, drug substances, hormones, lipophilic substances, polymers,proteins, peptides, toxins, vitamins, viral proteins or combinationsthereof.

115. The oligonucleotide conjugate of embodiment 113 or 114, wherein theconjugate moiety is an antibody or antibody fragment.

116. The oligonucleotide conjugate of embodiment 115, wherein theantibody or antibody fragment has affinity to the transferrin receptor.

117. The oligonucleotide conjugate of embodiment 113-115, comprising alinker which is positioned between the oligonucleotide and the conjugatemoiety.

118. The oligonucleotide conjugate of embodiment 117, wherein the linkeris a physiologically labile linker.

119. The oligonucleotide conjugate of embodiment 118, wherein thephysiologically labile linker is nuclease susceptible linker.

120. The oligonucleotide conjugate of embodiment 118 or 119, wherein theoligonucleotide has the formula D-F-G-F′ or F-G-F′-D′, wherein F, F′ andG are as defined in embodiments 73-80 and D or D′ comprises 1, 2 or 3DNA nucleosides with phosphorothioate internucleoside linkages.

121. The oligonucleotide conjugate of embodiment 113-120, which displayimproved uptake into the brain of the conjugate oligonucleotide ascompared to an unconjugated oligonucleotide.

122. A pharmaceutical composition comprising the oligonucleotide ofembodiment 1-112 or a conjugate of embodiment 113-121 and apharmaceutically acceptable diluent, carrier, salt and/or adjuvant.

123. A method for manufacturing the oligonucleotide of embodiment 1-112,comprising reacting nucleotide units thereby forming covalently linkedcontiguous nucleotide units comprised in the oligonucleotide.

124. The method of embodiment 123, further comprising reacting thecontiguous nucleotide sequence with a non-nucleotide conjugation moiety.

125. A method for manufacturing the composition of embodiment 122,comprising mixing the oligonucleotide with a pharmaceutically acceptablediluent, carrier, salt and/or adjuvant.

126. An in vivo or in vitro method for inducing UBE3A expression in atarget cell where expression of paternal UBE3A is suppressed, saidmethod comprising administering an oligonucleotide of any one ofembodiments 1-112 or a conjugate of embodiment 113-121 or thepharmaceutical composition of embodiment 122 in an effective amount tosaid cell.

127. The method of embodiment 126, wherein the expression of UBE3A isincreased by at least 40% compared to a control.

128. The method of embodiment 126 or 127, wherein the level of theSNHG14 transcript downstream of SNORD109B is reduced by at least 30%compared to a control.

129. The method of embodiment 126-128, wherein the target cell is aneuronal cell.

130. The method of embodiment 126-129, wherein the expression ofSNORD115 is not significantly affected compared to a control.

131. A method for treating or preventing a disease comprisingadministering a therapeutically or prophylactically effective amount ofan oligonucleotide of embodiment 1-112 or a conjugate of embodiment113-121 or the pharmaceutical composition of embodiment 122 to a subjectsuffering from or susceptible to the disease.

132. The oligonucleotide of embodiment 1-112 or a conjugate ofembodiment 113-121 or the pharmaceutical composition of embodiment 122,for use as a medicament for treatment or prevention of a disease in asubject.

133. Use of the oligonucleotide of oligonucleotide of embodiment 1-112or a conjugate of embodiment 113-121 for the preparation of a medicamentfor treatment or prevention of a disease in a subject.

134. The method, the oligonucleotide or the use of embodiments 131-133,wherein the disease is associated with in vivo activity of UBE3A.

135. The method, the oligonucleotide or the use of embodiments 131-134,wherein the disease is associated with reduced expression of UBE3Aand/or reduced activity of UBE3A in neuronal cells.

136. The method, the oligonucleotide or the use of embodiment 135,wherein the reduced expression of UBE3A and/or reduced activity of UBE3Ais due to mutations in the maternal allele of the UBE3A gene.

137. The method, the oligonucleotide or the use of embodiments 134-136,wherein the UBE3A expression is increased by at least 30%, or at least50%, or at least 70%, or at least 90%, or at least 100%, or at least150% or at least 200%, compared to the expression without theoligonucleotide of embodiment 1-112 or a conjugate of embodiment 113-121or the pharmaceutical composition of embodiment 122.

138. The method, the oligonucleotide or the use of embodiments 131-137,wherein the disease is Angelman syndrome.

139. The method, the oligonucleotide or the use of embodiments 131-138,wherein the subject is a mammal.

140. The method, the oligonucleotide or the use of embodiment 139,wherein the mammal is human.

141. The method, the oligonucleotide or the use of embodiment 139 or140, wherein the subject is an infant or a juvenile.

EXAMPLES

Materials and methods

TABLE 3List of oligonucleotides or contiguous nucleobase sequences complementary to SEQID NO: 1 (motif sequences indicated by SEQ ID NO), oligonucleotide designs made from these,as well as specific oligonucleotide compounds (indicated by CMP ID NO) designed based onthe motif sequence. Start Seq CMP SEQ ID ID NO Motif Design CompoundID NO ΔG° NO 1 4 AACTTCATCAATATTTCCC 3-13-3 AACttcatcaatatttCCC 4_1-23.36 1677 4 AACTTCATCAATATTTCCC 2-15-2 AActtcatcaatatttcCC 4_2 -19.601677 5 ACTTCATCAATATTTCCC 3-12-3 ACTtcatcaatatttCCC 5_1 -23.80 1677 5ACTTCATCAATATTTCCC 2-14-2 ACttcatcaatatttcCC 5_2 -20.24 1677 6CAACTTCATCAATATTTCCC 2-14-4 CAacttcatcaatattTCCC 6_1 -25.64 1677 6CAACTTCATCAATATTTCCC 2-16-2 CAacttcatcaatatttcCC 6_2 -22.28 1677 7CAACTTCATCAATATTTCC 4-13-2 CAACttcatcaatatttCC 7_1 -21.47 1678 7CAACTTCATCAATATTTCC 2-15-2 CAacttcatcaatatttCC 7_2 -19.46 1678 8CCAACTTCATCAATATTTCC 3-14-3 CCAacttcatcaatattTCC 8_1 -25.64 1678 9CCCAACTTCATCAATATTTC 4-14-2 CCCAacttcatcaatattTC 9_1 -25.64 1679 10ACCCAACTTCATCAATATTT 2-16-2 ACccaacttcatcaatatTT 10_1 -20.05 1680 11CCCAACTTCATCAATATTT 4-13-2 CCCAacttcatcaatatTT 11_1 -23.96 1680 11CCCAACTTCATCAATATTT 2-15-2 CCcaacttcatcaatatTT 11_2 -20.28 1680 12ACCCAACTTCATCAATATT 4-13-2 ACCCaacttcatcaataTT 12_1 -23.64 1681 12ACCCAACTTCATCAATATT 2-15-2 ACccaacttcatcaataTT 12_2 -19.18 1681 13CCCAACTTCATCAATATT 4-12-2 CCCAacttcatcaataTT 13_1 -23.09 1681 13CCCAACTTCATCAATATT 2-14-2 CCcaacttcatcaataTT 13_2 -19.41 1681 14TACCCAACTTCATCAATAT 2-15-2 TAcccaacttcatcaatAT 14_1 -19.31 1682 15TACCCAACTTCATCAATA 2-14-2 TAcccaacttcatcaaTA 15_1 -19.14 1683 16TTACCCAACTTCATCAATA 2-15-2 TTacccaacttcatcaaTA 16_1 -19.74 1683 17TTTACCCAACTTCATCAAT 4-13-2 TTTAcccaacttcatcaAT 17_1 -21.68 1684 17TTTACCCAACTTCATCAAT 2-15-2 TTtacccaacttcatcaAT 17_2 -19.22 1684 18ATACTTTACCCAACTTCAT 3-13-3 ATActttacccaacttCAT 18_1 -23.44 1688 18ATACTTTACCCAACTTCAT 2-15-2 ATactttacccaacttcAT 18_2 -20.13 1688 19TACTTTACCCAACTTCAT 3-12-3 TACtttacccaacttCAT 19_1 -22.78 1688 19TACTTTACCCAACTTCAT 2-14-2 TActttacccaacttcAT 19_2 -19.30 1688 20TTATACTTTACCCAACTTCA 2-16-2 TTatactttacccaacttCA 20_1 -21.40 1689 21TCACTGTTCTGACTTT 3-10-3 TCActgttctgacTTT 21_1 -19.11 1712 22TTCAATCTCTATCTCATCAT 2-16-2 TTcaatctctatctcatcAT 22_1 -19.42 4169 23CTTCAATCTCTATCTCATCA 4-14-2 CTTCaatctctatctcatCA 23_1 -24.21 4170 23CTTCAATCTCTATCTCATCA 2-16-2 CTtcaatctctatctcatCA 23_2 -22.04 4170 24TTCAATCTCTATCTCATCA 2-15-2 TTcaatctctatctcatCA 24_1 -19.44 4170 25CTTCAATCTCTATCTCATC 2-15-2 CTtcaatctctatctcaTC 25_1 -19.87 4171 26ACTTCAATCTCTATCTCAT 3-13-3 ACTtcaatctctatctCAT 26_1 -22.36 4172 26ACTTCAATCTCTATCTCAT 2-15-2 ACttcaatctctatctcAT 26_2 -19.08 4172 27CACTTCAATCTCTATCTCAT 2-16-2 CActtcaatctctatctcAT 27_1 -20.98 4172 28ACTTCAATCTCTATCTCA 2-12-4 ACttcaatctctatCTCA 28_1 -21.96 4173 28ACTTCAATCTCTATCTCA 2-14-2 ACttcaatctctatctCA 28_2 -19.10 4173 29CACTTCAATCTCTATCTCA 2-13-4 CActtcaatctctatCTCA 29_1 -23.86 4173 29CACTTCAATCTCTATCTCA 2-15-2 CActtcaatctctatctCA 29_2 -21.00 4173 30ACACTTCAATCTCTATCTC 2-15-2 ACacttcaatctctatcTC 30_1 -19.38 4174 31TACACTTCAATCTCTATCTC 2-14-4 TAcacttcaatctctaTCTC 31_1 -23.31 4174 31TACACTTCAATCTCTATCTC 2-16-2 TAcacttcaatctctatcTC 31_2 -20.53 4174 32TACACTTCAATCTCTATCT 4-13-2 TACActtcaatctctatCT 32_1 -22.34 4175 33CTTTGTCTCTCTTTACT 2-13-2 CTttgtctctctttaCT 33_1 -19.36 4374 34TATACCTTTCTTTAACCC 3-12-3 TATacctttctttaaCCC 34_1 -24.89 8118 34TATACCTTTCTTTAACCC 2-14-2 TAtacctttctttaacCC 34_2 -20.83 8118 34TATACCTTTCTTTAACCC 1-3-1-7-1-1-1-1-2 TataCctttcttTaAcCC 34_3 -21.63 811634 TATACCTTTCTTTAACCC 1-4-1-6-1-3-2 TatacCtttcttTaacCC 34_4 -21.31 811634 TATACCTTTCTTTAACCC 1-2-1-1-1-7-2-1-2 TatAcCtttctttAAcCC 34_5 -21.518116 34 TATACCTTTCTTTAACCC 2-3-1-7-1-2-2 TAtacCtttctttAacCC 34_6 -21.848116 34 TATACCTTTCTTTAACCC 2-13-3 TAtacctttctttaaCCC 34_7 -23.21 8116 35TGTTTATACCCTTTCC 2-12-2 TGtttataccctttCC 35_1 -20.33 9212 35TGTTTATACCCTTTCC 4-10-2 TGTTtataccctttCC 35_2 -22.69 9212 36TCTCCTTTATGACTCC 2-10-4 TCtcctttatgaCTCC 36_1 -23.29 10839 37CTTCTCCTTTATGACTC 2-13-2 CTtctcctttatgacTC 37_1 -19.26 10840 38CCATTTATTTCCATTTATT 4-13-2 CCATttatttccatttaTT 38_1 -22.32 15567 38CCATTTATTTCCATTTATT 2-15-2 CCatttatttccatttaTT 38_2 -19.61 15567 38CCATTTATTTCCATTTATT 1-2-1-9-2-1-3 CcaTttatttccaTTtATT 38_3 -20.02 1556738 CCATTTATTTCCATTTATT 1-1-1-1-1-8-1-1-1-1-2 CcAtTtatttccaTtTaTT 38_4-18.95 15567 38 CCATTTATTTCCATTTATT 2-2-1-8-1-3-2 CCatTtatttccaTttaTT38_5 -20.35 15567 38 CCATTTATTTCCATTTATT 1-2-3-6-1-3-3CcaTTTatttccAtttATT 38_6 -20.87 15567 39 CTTTCCATTTATTTCCATTT 2-14-4CTttccatttatttccATTT 39_1 -23.14 15570 39 CTTTCCATTTATTTCCATTT1-13-1-1-1-1-2 CtttccatttatttCcAtTT 39_2 -20.96 15570 39CTTTCCATTTATTTCCATTT 1-13-1-3-2 CtttccatttatttCcatTT 39_3 -20.91 1557039 CTTTCCATTTATTTCCATTT 1-3-1-1-1-11-2 CtttCcAtttatttccatTT 39_4 -20.9615570 39 CTTTCCATTTATTTCCATTT 1-1-1-3-1-9-1-1-2 CtTtccAtttatttccAtTT39_5 -20.54 15570 40 TCTTTCCATTTATTTCCATT 2-14-4 TCtttccatttatttcCATT40_1 -24.62 15571 40 TCTTTCCATTTATTTCCATT 2-13-1-1-3TCtttccatttatttCcATT 40_2 -23.39 15571 40 TCTTTCCATTTATTTCCATT2-13-1-2-2 TCtttccatttatttCcaTT 40_3 -22.53 15571 40TCTTTCCATTTATTTCCATT 2-14-1-1-2 TCtttccatttatttcCaTT 40_4 -22.34 1557140 TCTTTCCATTTATTTCCATT 2-3-1-11-3 TCtttCcatttatttccATT 40_5 -23.3915571 40 TCTTTCCATTTATTTCCATT 2-4-1-10-3 TCtttcCatttatttccATT 40_6-23.20 15571 40 TCTTTCCATTTATTTCCATT 2-3-1-12-2 TCtttCcatttatttccaTT40_7 -22.53 15571 40 TCTTTCCATTTATTTCCATT 2-4-1-11-2TCtttcCatttatttccaTT 40_8 -22.34 15571 41 ATTACCCATCCGTTCT 2-12-2ATtacccatccgttCT 41_1 -21.15 21965 42 GCATTAGGCACATTACAT 3-12-3GCAttaggcacattaCAT 42_1 -23.96 22211 43 ATTATTATTTAACCTTCCTA 2-16-2ATtattatttaaccttccTA 43_1 -19.28 30451 44 ACATTATTATTTAACCTTCC 4-14-2ACATtattatttaaccttCC 44_1 -22.84 30453 44 ACATTATTATTTAACCTTCC 2-16-2ACattattatttaaccttCC 44_2 -20.13 30453 45 CATTATTATTTAACCTTCC 4-13-2CATTattatttaaccttCC 45_1 -22.04 30453 45 CATTATTATTTAACCTTCC 2-15-2CAttattatttaaccttCC 45_2 -19.55 30453 46 CCTCTGCTTATAACTTT 2-13-2CCtctgcttataactTT 46_1 -19.15 30699 47 CTACTATACTTTCCTCT 2-11-4CTactatactttcCTCT 47_1 -22.32 30711 48 GTTCTACTATACTTTCC 4-11-2GTTCtactatactttCC 48_1 -21.69 30714 48 GTTCTACTATACTTTCC 2-13-2GTtctactatactttCC 48_2 -19.21 30714 48 GTTCTACTATACTTTCC 1-2-1-7-2-2-2GttCtactataCTttCC 48_3 -20.83 30712 48 GTTCTACTATACTTTCC 2-9-1-3-2GTtctactataCtttCC 48_4 -20.20 30712 48 GTTCTACTATACTTTCC 1-2-1-9-1-1-2GttCtactatactTtCC 48_5 -18.95 30712 48 GTTCTACTATACTTTCC 2-1-1-10-3GTtCtactatacttTCC 48_6 -21.18 30712 48 GTTCTACTATACTTTCC 1-3-1-10-2GttcTactatactttCC 48_7 -18.61 30712 49 CACCTGATAACAGACCCT 3-12-3CACctgataacagacCCT 49_1 -26.38 36068 50 CACCTGATAACAGACC 3-10-3CACctgataacagACC 50_1 -21.10 36070 51 CCCACCAAAGGATATATT 3-12-3CCCaccaaaggatatATT 51_1 -23.47 37208 52 ACCAGCTACAGGAACCTC 3-12-3ACCagctacaggaacCTC 52_1 -26.57 46132 53 CTATATCTCACTCCTATTT 4-13-2CTATatctcactcctatTT 53_1 -23.07 48143 53 CTATATCTCACTCCTATTT 2-13-4CTatatctcactcctATTT 53_2 -22.12 48143 54 CTATATCTCACTCCTATT 2-14-2CTatatctcactcctaTT 54_1 -19.40 48144 54 CTATATCTCACTCCTATT 2-12-4CTatatctcactccTATT 54_2 -22.28 48144 54 CTATATCTCACTCCTATT 3-12-3CTAtatctcactcctATT 54_3 -21.44 48144 55 CTACTATATCTCACTCCTAT 2-16-2CTactatatctcactcctAT 55_1 -22.00 48145 55 CTACTATATCTCACTCCTAT 2-14-4CTactatatctcactcCTAT 55_2 -25.54 48145 56 TACTATATCTCACTCCTAT 2-13-4TActatatctcactcCTAT 56_1 -23.29 48145 57 CTACTATATCTCACTCCTA 2-15-2CTactatatctcactccTA 57_1 -21.91 48146 58 TACTATATCTCACTCCTA 2-14-2TActatatctcactccTA 58_1 -19.66 48146 58 TACTATATCTCACTCCTA 2-12-4TActatatctcactCCTA 58_2 -23.59 48146 58 TACTATATCTCACTCCTA 3-12-3TACtatatctcactcCTA 58_3 -22.62 48146 59 CTACTATATCTCACTCCT 2-14-2CTactatatctcactcCT 59_1 -21.25 48147 59 CTACTATATCTCACTCCT 4-12-2CTACtatatctcactcCT 59_2 -23.87 48147 60 CTACTATATCTCACTCC 2-13-2CTactatatctcactCC 60_1 -20.13 48148 60 CTACTATATCTCACTCC 2-11-4CTactatatctcaCTCC 60_2 -23.00 48148 60 CTACTATATCTCACTCC 3-11-3CTActatatctcacTCC 60_3 -22.56 48148 61 CCTACTATATCTCACTC 2-11-4CCtactatatctcACTC 61_1 -21.93 48149 62 CTCCTACTATATCTCACTC 4-13-2CTCCtactatatctcacTC 62_1 -25.69 48149 63 TCCTACTATATCTCACTC 3-12-3TCCtactatatctcaCTC 63_1 -23.88 48149 64 CTCCTACTATATCTCACT 4-12-2CTCCtactatatctcaCT 64_1 -24.87 48150 64 CTCCTACTATATCTCACT 3-12-3CTCctactatatctcACT 64_2 -22.93 48150 65 TTTCCTCTCCTACTATATC 2-15-2TTtcctctcctactataTC 65_1 -21.23 48155 66 ATCCATATCCTTTCCT 3-10-3ATCcatatcctttCCT 66_1 -24.02 48168 67 CATCCATATCCTTTCCT 4-11-2CATCcatatcctttcCT 67_1 -24.94 48168 68 ATCATCCATATCCTTTCC 4-12-2ATCAtccatatcctttCC 68_1 -25.69 48169 69 CATCATCCATATCCTTTC 4-12-2CATCatccatatccttTC 69_1 -23.32 48170 69 CATCATCCATATCCTTTC 2-14-2CAtcatccatatccttTC 69_2 -20.72 48170 69 CATCATCCATATCCTTTC 2-12-4CAtcatccatatccTTTC 69_3 -22.56 48170 70 TACATCATCCATATCCTTTC 2-16-2TAcatcatccatatccttTC 70_1 -22.45 48170 70 TACATCATCCATATCCTTTC 4-14-2TACAtcatccatatccttTC 70_2 -25.00 48170 70 TACATCATCCATATCCTTTC 2-14-4TAcatcatccatatccTTTC 70_3 -24.29 48170 71 ACATCATCCATATCCTTT 3-12-3ACAtcatccatatccTTT 71_1 -22.11 48171 72 CATCATCCATATCCTTT 2-13-2CAtcatccatatcctTT 72_1 -19.04 48171 72 CATCATCCATATCCTTT 4-11-2CATCatccatatcctTT 72_2 -21.64 48171 73 TACATCATCCATATCCTTT 2-15-2TAcatcatccatatcctTT 73_1 -20.76 48171 73 TACATCATCCATATCCTTT 2-13-4TAcatcatccatatcCTTT 73_2 -23.36 48171 73 TACATCATCCATATCCTTT 3-13-3TACatcatccatatccTTT 73_3 -22.88 48171 74 ATACATCATCCATATCCTT 2-15-2ATacatcatccatatccTT 74_1 -20.80 48172 74 ATACATCATCCATATCCTT 4-13-2ATACatcatccatatccTT 74_2 -23.12 48172 75 TACATCATCCATATCCTT 2-14-2TAcatcatccatatccTT 75_1 -19.97 48172 75 TACATCATCCATATCCTT 4-12-2TACAtcatccatatccTT 75_2 -22.52 48172 76 TATACATCATCCATATCCTT 2-16-2TAtacatcatccatatccTT 76_1 -21.36 48172 77 ATACATCATCCATATCCT 3-12-3ATAcatcatccatatCCT 77_1 -24.15 48173 77 ATACATCATCCATATCCT 2-14-2ATacatcatccatatcCT 77_2 -20.55 48173 77 ATACATCATCCATATCCT 2-13-3ATacatcatccatatCCT 77_3 -22.92 48173 78 ATATACATCATCCATATCCT 2-16-2ATatacatcatccatatcCT 78_1 -22.04 48173 79 TACATCATCCATATCCT 2-11-4TAcatcatccataTCCT 79_1 -23.21 48173 79 TACATCATCCATATCCT 2-13-2TAcatcatccatatcCT 79_2 -19.71 48173 79 TACATCATCCATATCCT 4-11-2TACAtcatccatatcCT 79_3 -22.27 48173 80 TATACATCATCCATATCCT 2-15-2TAtacatcatccatatcCT 80_1 -21.11 48173 80 TATACATCATCCATATCCT 3-13-3TATacatcatccatatCCT 80_2 -25.15 48173 80 TATACATCATCCATATCCT 4-13-2TATAcatcatccatatcCT 80_3 -24.01 48173 81 ATACATCATCCATATCC 3-11-3ATAcatcatccataTCC 81_1 -21.79 48174 82 ATATACATCATCCATATCC 4-13-2ATATacatcatccatatCC 82_1 -23.73 48174 82 ATATACATCATCCATATCC 2-15-2ATatacatcatccatatCC 82_2 -20.93 48174 83 TATACATCATCCATATCC 2-14-2TAtacatcatccatatCC 83_1 -20.00 48174 83 TATACATCATCCATATCC 4-12-2TATAcatcatccatatCC 83_2 -22.90 48174 84 TATATACATCATCCATATCC 2-16-2TAtatacatcatccatatCC 84_1 -21.49 48174 84 TATATACATCATCCATATCC 4-14-2TATAtacatcatccatatCC 84_2 -24.29 48174 85 GCTTCATATTTCTCCA 2-12-2GCttcatatttctcCA 85_1 -20.44 49345 85 GCTTCATATTTCTCCA 2-11-3GCttcatatttctCCA 85_2 -22.81 49345 86 CATCTTGTTCTTTACCT 2-13-2CAtcttgttctttacCT 86_1 -19.67 49581 87 TATATTCACCATTGCC 2-10-4TAtattcaccatTGCC 87_1 -22.70 49724 88 CCTTATATTCACCATTG 2-13-2CCttatattcaccatTG 88_1 -19.44 49726 88 CCTTATATTCACCATTG 2-11-4CCttatattcaccATTG 88_2 -21.25 49726 89 CCTCCTTATATTCACC 4-10-2CCTCcttatattcaCC 89_1 -24.64 49730 go CCCTTCCTTTATTCAA 3-10-3CCCttcctttattCAA 90_1 -23.86 50189 gi CCTTACTGTTAAATCCT 2-13-2CCttactgttaaatcCT 91_1 -19.81 50475 92 CAGGCAGATAACCTCCAA 3-12-3CAGgcagataacctcCAA 92_1 -25.31 52419 93 CAGCAGGCAGATAACCTC 3-12-3CAGcaggcagataacCTC 93_1 -25.88 52422 94 CGAATCTTGACATACAGG 3-12-3CGAatcttgacatacAGG 94_1 -21.47 53955 95 CTCATACTTGCTTTAAT 4-11-2CTCAtacttgctttaAT 95_1 -19.10 60821 95 CTCATACTTGCTTTAAT 2-13-2CTcatacttgctttaAT 95_2 -16.35 60821 96 ACATCTCATACTTGCTT 2-11-4ACatctcatacttGCTT 96_1 -21.31 60825 96 ACATCTCATACTTGCTT 2-13-2ACatctcatacttgcTT 96_2 -17.66 60825 96 ACATCTCATACTTGCTT 2-12-3ACatctcatacttgCTT 96_3 -19.52 60825 97 ACATCTCATACTTGCT 2-10-4ACatctcatactTGCT 97_1 -21.18 60826 97 ACATCTCATACTTGCT 2-12-2ACatctcatacttgCT 97_2 -17.70 60826 97 ACATCTCATACTTGCT 2-11-3ACatctcatacttGCT 97_3 -19.49 60826 97 ACATCTCATACTTGCT 4-10-2ACATctcatacttgCT 97_4 -20.48 60826 98 TACATCTCATACTTGCT 2-11-4TAcatctcatactTGCT 98_1 -22.33 60826 98 TACATCTCATACTTGCT 2-13-2TAcatctcatacttgCT 98_2 -18.85 60826 98 TACATCTCATACTTGCT 4-11-2TACAtctcatacttgCT 98_3 -21.40 60826 gg CCTACATCTCATACTTGC 3-12-3CCTacatctcatactTGC gg_1 -26.29 60827 gg CCTACATCTCATACTTGC 2-14-2CCtacatctcatacttGC 99_2 -22.98 60827 gg CCTACATCTCATACTTGC 2-13-3CCtacatctcatactTGC 99_3 -24.67 60827 gg CCTACATCTCATACTTGC 2-12-4CCtacatctcatacTTGC 99_4 -25.70 60827 100 CTACATCTCATACTTGC 3-11-3CTAcatctcatactTGC 100_1 -22.33 60827 100 CTACATCTCATACTTGC 2-13-2CTacatctcatacttGC 100_2 -19.41 60827 100 CTACATCTCATACTTGC 2-12-3CTacatctcatactTGC 100_3 -21.10 60827 101 TACATCTCATACTTGC 3-10-3TACatctcatactTGC 101_1 -19.94 60827 101 TACATCTCATACTTGC 2-12-2TAcatctcatacttGC 101_2 -17.15 60827 101 TACATCTCATACTTGC 2-11-3TAcatctcatactTGC 101_3 -18.85 60827 101 TACATCTCATACTTGC 4-10-2TACAtctcatacttGC 101_4 -19.71 60827 102 CCTACATCTCATACTTG 4-11-2CCTAcatctcatactTG 102_1 -22.52 60828 102 CCTACATCTCATACTTG 2-13-2CCtacatctcatactTG 102_2 -19.67 60828 102 CCTACATCTCATACTTG 3-12-2CCTacatctcatactTG 102_3 -21.29 60828 102 CCTACATCTCATACTTG 3-11-3CCTacatctcatacTTG 102_4 -22.31 60828 103 ACCTACATCTCATACTT 3-11-3ACCtacatctcataCTT 103_1 -21.93 60829 103 ACCTACATCTCATACTT 2-13-2ACctacatctcatacTT 103_2 -17.76 60829 103 ACCTACATCTCATACTT 2-11-4ACctacatctcatACTT 103_3 -20.03 60829 103 ACCTACATCTCATACTT 3-12-2ACCtacatctcatacTT 103_4 -20.26 60829 104 CCTACATCTCATACTT 3-10-3CCTacatctcataCTT 104_1 -21.50 60829 104 CCTACATCTCATACTT 2-12-2CCtacatctcatacTT 104_2 -18.21 60829 104 CCTACATCTCATACTT 2-10-4CCtacatctcatACTT 104_3 -20.48 60829 105 TACCTACATCTCATACTT 4-12-2TACCtacatctcatacTT 105_1 -22.49 60829 105 TACCTACATCTCATACTT 2-14-2TAcctacatctcatacTT 105_2 -18.81 60829 105 TACCTACATCTCATACTT 2-13-3TAcctacatctcataCTT 105_3 -20.48 60829 105 TACCTACATCTCATACTT 2-12-4TAcctacatctcatACTT 105_4 -21.08 60829 106 TTACCTACATCTCATACTT 3-13-3TTAcctacatctcataCTT 106_1 -22.30 60829 106 TTACCTACATCTCATACTT 2-15-2TTacctacatctcatacTT 106_2 -19.40 60829 106 TTACCTACATCTCATACTT 2-14-3TTacctacatctcataCTT 106_3 -21.08 60829 106 TTACCTACATCTCATACTT 2-13-4TTacctacatctcatACTT 106_4 -21.67 60829 107 ACCTACATCTCATACT 4-10-2ACCTacatctcataCT 107_1 -21.72 60830 107 ACCTACATCTCATACT 2-12-2ACctacatctcataCT 107_2 -17.61 60830 107 ACCTACATCTCATACT 3-11-2ACCtacatctcataCT 107_3 -20.10 60830 107 ACCTACATCTCATACT 2-10-4ACctacatctcaTACT 107_4 -20.11 60830 108 TACCTACATCTCATACT 4-11-2TACCtacatctcataCT 108_1 -22.34 60830 108 TACCTACATCTCATACT 2-13-2TAcctacatctcataCT 108_2 -18.66 60830 108 TACCTACATCTCATACT 3-12-2TACctacatctcataCT 108_3 -19.85 60830 108 TACCTACATCTCATACT 3-11-3TACctacatctcatACT 108_4 -20.44 60830 109 TTACCTACATCTCATACT 2-12-4TTacctacatctcaTACT 109_1 -21.75 60830 109 TTACCTACATCTCATACT 2-14-2TTacctacatctcataCT 109_2 -19.25 60830 109 TTACCTACATCTCATACT 3-13-2TTAcctacatctcataCT 109_3 -20.48 60830 109 TTACCTACATCTCATACT 3-12-3TTAcctacatctcatACT 109_4 -21.08 60830 110 TTACCTACATCTCATAC 3-11-3TTAcctacatctcaTAC 110_1 -19.50 60831 110 TTACCTACATCTCATAC 2-13-2TTacctacatctcatAC 110_2 -16.37 60831 111 GTTACCTACATCTCATA 2-11-4GTtacctacatctCATA 111_1 -21.69 60832 111 GTTACCTACATCTCATA 2-13-2GTtacctacatctcaTA 111_2 -18.74 60832 111 GTTACCTACATCTCATA 3-12-2GTTacctacatctcaTA 111_3 -19.98 60832 112 GTTACCTACATCTCAT 3-10-3GTTacctacatctCAT 112_1 -20.69 60833 112 GTTACCTACATCTCAT 2-12-2GTtacctacatctcAT 112_2 -17.37 60833 113 ATATACCCAAAGGCACCT 3-12-3ATAtacccaaaggcaCCT 113_1 -25.99 62200 114 TCTACTCATCCTTTAACTCA 2-14-4TCtactcatcctttaaCTCA 114_1 -25.63 62251 115 CCTTAATCTGTATCACT 2-13-2CCttaatctgtatcaCT 115_1 -19.58 62286 116 CCATACACAGCACATA 2-12-2CCatacacagcacaTA 116_1 -19.04 62424 117 CTCCATACACAGCACAT 2-13-2CTccatacacagcacAT 117_1 -20.08 62425 118 CAGAATAATTCTCCTCC 2-13-2CAgaataattctcctCC 118_1 -19.86 62441 119 GTCCTACATATATACC 4-10-2GTCCtacatatataCC 119_1 -22.09 66380 120 TGCTTCCTTACTAACC 4-10-2TGCTtccttactaaCC 120_1 -23.93 66701 120 TGCTTCCTTACTAACC 2-12-2TGcttccttactaaCC 120_2 -20.10 66701 121 CCCTTTGTAATCATCT 4-10-2CCCTttgtaatcatCT 121_1 -23.44 66838 122 TCCCTTTGTAATCATCT 2-13-2TCcctttgtaatcatCT 122_1 -19.97 66838 123 CTGCCATCAATACCAT 2-12-2CTgccatcaataccAT 123_1 -19.14 68918 124 TCACTGCCATCAATACC 2-13-2TCactgccatcaataCC 124_1 -21.35 68920 125 ATTCTTACTTTATTCCTCA 2-15-2ATtcttactttattcctCA 125_1 -20.16 70033 126 TCACTTTCCAGATATCA 4-11-2TCACtttccagatatCA 126_1 -21.61 77567 126 TCACTTTCCAGATATCA 2-13-2TCactttccagatatCA 126_2 -18.65 77567 127 TCCTTCAAATTCCACATAC 3-13-3TCCttcaaattccacaTAC 127_1 -24.09 82053 128 ACATGTCCCTTTATATT 4-11-2ACATgtccctttataTT 128_1 -20.87 92323 128 ACATGTCCCTTTATATT 2-13-2ACatgtccctttataTT 128_2 -17.66 92323 128 ACATGTCCCTTTATATT 3-12-2ACAtgtccctttataTT 128_3 -19.13 92323 128 ACATGTCCCTTTATATT 3-11-3ACAtgtccctttatATT 128_4 -20.03 92323 129 ACATGTCCCTTTATAT 3-10-3ACAtgtccctttaTAT 129_1 -20.11 92324 129 ACATGTCCCTTTATAT 2-12-2ACatgtccctttatAT 129_2 -16.74 92324 130 CCAAGAAAGGAGCAAGCT 3-12-3CCAagaaaggagcaaGCT 130_1 -25.26 97146 131 TCCAAGAAAGGAGCAAGC 3-12-3TCCaagaaaggagcaAGC 131_1 -24.12 97147 132 CTCATCCCTCCAAGAAA 4-11-2CTCAtccctccaagaAA 132_1 -22.58 97156 132 CTCATCCCTCCAAGAAA 2-13-2CTcatccctccaagaAA 132_2 -19.83 97156 132 CTCATCCCTCCAAGAAA 3-12-2CTCatccctccaagaAA 132_3 -21.11 97156 133 TCATCCCTCCAAGAAA 4-10-2TCATccctccaagaAA 133_1 -20.41 97156 133 TCATCCCTCCAAGAAA 2-12-2TCatccctccaagaAA 133_2 -17.63 97156 133 TCATCCCTCCAAGAAA 3-11-2TCAtccctccaagaAA 133_3 -19.09 97156 133 TCATCCCTCCAAGAAA 3-10-3TCAtccctccaagAAA 133_4 -19.81 97156 134 CACCTCCCTATTACATAAA 4-13-2CACCtccctattacataAA 134_1 -24.18 100018 134 CACCTCCCTATTACATAAA 2-15-2CAcctccctattacataAA 134_2 -20.51 100018 135 CACCTCCCTATTACATAA 4-12-2CACCtccctattacatAA 135_1 -23.75 100019 135 CACCTCCCTATTACATAA 2-14-2CAcctccctattacatAA 135_2 -20.07 100019 136 CCTCCCTATTACATAA 2-12-2CCtccctattacatAA 136_1 -18.40 100019 137 CTAAATCTTCCAATTCATA 2-15-2CTaaatcttccaattcaTA 137_1 -18.12 106139 138 TATCCCTTGATTATCCT 2-13-2TAtcccttgattatcCT 138_1 -20.68 109406 139 CCTCTTTGTCAAATACT 2-13-2CCtctttgtcaaataCT 139_1 -19.30 110768 140 CAGCTTATTTACCTCTT 2-13-2CAgcttatttacctcTT 140_1 -19.30 114828 141 ACTCTTTACCTCTAACACT 4-13-2ACTCtttacctctaacaCT 141_1 -24.26 117468 142 TTACTCTTTACCTCTAACAC 3-14-3TTActctttacctctaaCAC 142_1 -23.23 117469 143 CCAACCTAATACCTTAATA 2-15-2CCaacctaataccttaaTA 143_1 -20.27 118639 144 TACCAACCTAATACCTTAA 2-15-2TAccaacctaataccttAA 144_1 -18.32 118641 145 CCAATACCCACAAACC 3-10-3CCAatacccacaaACC 145_1 -23.17 124162 145 CCAATACCCACAAACC 2-12-2CCaatacccacaaaCC 145_2 -20.85 124162 146 CCATTATTCTACTTTGT 3-11-3CCAttattctacttTGT 146_1 -21.79 125501 146 CCATTATTCTACTTTGT 2-13-2CCattattctactttGT 146_2 -18.63 125501 147 CATTTCCTTATCTTCACA 2-14-2CAtttccttatcttcaCA 147_1 -20.39 125529 148 TCATTTCCTTATCTTCACA 4-13-2TCATttccttatcttcaCA 148_1 -24.13 125529 149 AATAATTCCTCATTTCCT 2-14-2AAtaattcctcatttcCT 149_1 -18.01 125539 150 ACAATAATTCCTCATTTCC 3-13-3ACAataattcctcattTCC 150_1 -22.71 125540 150 ACAATAATTCCTCATTTCC 2-15-2ACaataattcctcatttCC 150_2 -20.23 125540 151 TATTGAACCAATTCTA 3-10-3TATtgaaccaattCTA 151_1 -16.93 4806 152 CATATTGAACCAATTC 4-10-2CATAttgaaccaatTC 152_1 -16.32 4808 153 TCATATTGAACCAATT 4-10-2TCATattgaaccaaTT 153_1 -16.14 4809 154 CATCATATTGAACCAA 2-10-4CAtcatattgaaCCAA 154_1 -17.65 4811 155 TCATCATATTGAACCA 3-10-3TCAtcatattgaaCCA 155_1 -19.40 4812 156 CACAATCAACAACAAATA 4-12-2CACAatcaacaacaaaTA 156_1 -16.16 4972 157 TACACAATCAACAACAAAT 4-13-2TACAcaatcaacaacaaAT 157_1 -16.76 4973 158 CTGTACACAATCAACA 4-10-2CTGTacacaatcaaCA 158_1 -19.05 4979 159 CACTAATAATTCACTTT 4-11-2CACTaataattcactTT 159_1 -16.39 5058 160 CAACATTATTGACACT 2-10-4CAacattattgaCACT 160_1 -17.17 5071 161 AAACTTTCCCAACATTAT 2-12-4AAactttcccaacaTTAT 161_1 -18.69 5078 162 TCCTATATTCTCTTAAA 4-11-2TCCTatattctcttaAA 162_1 -18.58 5094 163 TTTCCTATATTCTCTTA 4-11-2TTTCctatattctctTA 163_1 -18.69 5096 164 CAAGTTTCCTATATTCT 4-11-2CAAGtttcctatattCT 164_1 -19.97 5100 165 CAAGTTTCCTATATTC 4-10-2CAAGtttcctatatTC 165_1 -17.47 5101 166 CATTCTATCTGCCAAA 2-10-4CAttctatctgcCAAA 166_1 -18.36 5218 167 CCATTCTATCTGCCAAA 2-11-4CCattctatctgcCAAA 167_1 -22.08 5218 168 TATAGCCATTCTATCT 4-10-2TATAgccattctatCT 168_1 -20.63 5224 169 TTATAGCCATTCTATCT 4-11-2TTATagccattctatCT 169_1 -20.82 5224 169 TTATAGCCATTCTATCT 1-10-3-1-2TtatagccattCTAtCT 169_2 -20.51 5224 169 TTATAGCCATTCTATCT 2-9-1-2-3TTatagccattCtaTCT 169_3 -20.12 5224 169 TTATAGCCATTCTATCT 1-1-1-8-2-1-3TtAtagccattCTaTCT 169_4 -20.59 5224 169 TTATAGCCATTCTATCT 1-3-1-6-2-2-2TtatAgccattCTatCT 169_5 -19.97 5224 169 TTATAGCCATTCTATCT 3-8-1-3-2TTAtagccattCtatCT 169_6 -20.13 5224 169 TTATAGCCATTCTATCT 1-10-2-2-2TtatagccattCTatCT 169_7 -19.37 5224 169 TTATAGCCATTCTATCT 2-9-1-1-4TTatagccattCtATCT 169_8 -21.02 5224 169 TTATAGCCATTCTATCT 1-1-1-8-1-1-4TtAtagccattCtATCT 169_9 -19.88 5224 169 TTATAGCCATTCTATCT 1-2-1-7-1-1-4TtaTagccattCtATCT 169_10 -20.65 5224 169 TTATAGCCATTCTATCT 1-3-1-6-1-1-4TtatAgccattCtATCT 169_11 -20.38 5224 169 TTATAGCCATTCTATCT 1-10-1-1-4TtatagccattCtATCT 169_12 -19.78 5224 169 TTATAGCCATTCTATCT 3-8-1-1-1-1-2TTAtagccattCtAtCT 169_13 -20.22 5224 169 TTATAGCCATTCTATCT2-1-1-7-1-1-1-1-2 TTaTagccattCtAtCT 169_14 -19.96 5224 169TTATAGCCATTCTATCT 2-2-1-6-1-1-1-1-2 TTatAgccattCtAtCT 169_15 -19.69 5224169 TTATAGCCATTCTATCT 2-9-1-1-1-1-2 TTatagccattCtAtCT 169_16 -19.09 5224169 TTATAGCCATTCTATCT 1-2-2-6-1-1-1-1-2 TtaTAgccattCtAtCT 169_17 -20.355224 169 TTATAGCCATTCTATCT 1-2-1-7-1-1-1-1-2 TtaTagccattCtAtCT 169_18-18.72 5224 169 TTATAGCCATTCTATCT 1-3-1-6-1-1-1-1-2 TtatAgccattCtAtCT169_19 -18.45 5224 169 TTATAGCCATTCTATCT 2-2-1-6-1-2-3 TTatAgccattCtaTCT169_20 -20.71 5224 169 TTATAGCCATTCTATCT 1-1-2-7-1-2-3 TtATagccattCtaTCT169_21 -20.65 5224 169 TTATAGCCATTCTATCT 1-1-1-1-1-6-1-2-3TtAtAgccattCtaTCT 169_22 -19.57 5224 169 TTATAGCCATTCTATCT 1-1-1-8-1-2-3TtAtagccattCtaTCT 169_23 -18.98 5224 169 TTATAGCCATTCTATCT 4-7-1-3-2TTATagccattCtatCT 169_24 -21.80 5224 169 TTATAGCCATTCTATCT 3-1-1-6-1-3-2TTAtAgccattCtatCT 169_25 -20.72 5224 169 TTATAGCCATTCTATCT 2-1-1-7-1-3-2TTaTagccattCtatCT 169_26 -19.86 5224 169 TTATAGCCATTCTATCT 2-2-1-6-1-3-2TTatAgccattCtatCT 169_27 -19.59 5224 169 TTATAGCCATTCTATCT 2-9-1-3-2TTatagccattCtatCT 169_28 -18.99 5224 169 TTATAGCCATTCTATCT 1-1-3-6-1-3-2TtATAgccattCtatCT 169_29 -21.16 5224 169 TTATAGCCATTCTATCT 1-1-2-7-1-3-2TtATagccattCtatCT 169_30 -19.53 5224 169 TTATAGCCATTCTATCT1-1-1-1-1-6-1-3-2 TtAtAgccattCtatCT 169_31 -18.45 5224 169TTATAGCCATTCTATCT 1-2-2-6-1-3-2 TtaTAgccattCtatCT 169_32 -20.25 5224 169TTATAGCCATTCTATCT 1-2-1-7-1-3-2 TtaTagccattCtatCT 169_33 -18.62 5224 169TTATAGCCATTCTATCT 1-3-1-6-1-3-2 TtatAgccattCtatCT 169_34 -18.35 5224 169TTATAGCCATTCTATCT 1-1-1-9-5 TtAtagccattcTATCT 169_35 -20.88 5224 169TTATAGCCATTCTATCT 2-10-2-1-2 TTatagccattcTAtCT 169_36 -20.09 5224 169TTATAGCCATTCTATCT 1-1-1-9-2-1-2 TtAtagccattcTAtCT 169_37 -18.95 5224 169TTATAGCCATTCTATCT 1-2-1-8-2-1-2 TtaTagccattcTAtCT 169_38 -19.72 5224 169TTATAGCCATTCTATCT 1-3-1-7-2-1-2 TtatAgccattcTAtCT 169_39 -19.44 5224 169TTATAGCCATTCTATCT 1-11-2-1-2 TtatagccattcTAtCT 169_40 -18.85 5224 169TTATAGCCATTCTATCT 3-9-1-1-3 TTAtagccattcTaTCT 169_41 -21.21 5224 169TTATAGCCATTCTATCT 1-1-1-9-1-1-3 TtAtagccattcTaTCT 169_42 -18.94 5224 169TTATAGCCATTCTATCT 3-9-1-2-2 TTAtagccattcTatCT 169_43 -20.09 5224 169TTATAGCCATTCTATCT 1-2-1-8-1-2-2 TtaTagccattcTatCT 169_44 -18.58 5224 169TTATAGCCATTCTATCT 1-3-1-7-1-2-2 TtatAgccattcTatCT 169_45 -18.31 5224 169TTATAGCCATTCTATCT 1-1-1-10-4 TtAtagccattctATCT 169_46 -18.90 5224 169TTATAGCCATTCTATCT 3-10-1-1-2 TTAtagccattctAtCT 169_47 -19.24 5224 169TTATAGCCATTCTATCT 2-11-1-1-2 TTatagccattctAtCT 169_48 -18.11 5224 169TTATAGCCATTCTATCT 1-2-2-8-1-1-2 TtaTAgccattctAtCT 169_49 -19.37 5224 169TTATAGCCATTCTATCT 3-1-1-10-2 TTAtAgccattctatCT 169_50 -19.74 5224 169TTATAGCCATTCTATCT 3-12-2 TTAtagccattctatCT 169_51 -19.15 5224 169TTATAGCCATTCTATCT 2-1-2-10-2 TTaTAgccattctatCT 169_52 -20.51 5224 169TTATAGCCATTCTATCT 2-1-1-11-2 TTaTagccattctatCT 169_53 -18.88 5224 169TTATAGCCATTCTATCT 2-2-1-10-2 TTatAgccattctatCT 169_54 -18.61 5224 169TTATAGCCATTCTATCT 2-13-2 TTatagccattctatCT 169_55 -18.02 5224 169TTATAGCCATTCTATCT 1-1-3-10-2 TtATAgccattctatCT 169_56 -20.18 5224 169TTATAGCCATTCTATCT 1-1-2-11-2 TtATagccattctatCT 169_57 -18.55 5224 169TTATAGCCATTCTATCT 2-9-3-1-2 TTatagccattCTAtCT 169_58 -21.75 5224 169TTATAGCCATTCTATCT 1-1-1-8-2-2-2 TtAtagccattCTatCT 169_59 -19.47 5224 169TTATAGCCATTCTATCT 1-2-2-6-2-2-2 TtaTAgccattCTatCT 169_60 -21.87 5224 169TTATAGCCATTCTATCT 1-1-3-6-1-1-1-1-2 TtATAgccattCtAtCT 169_61 -21.25 5224169 TTATAGCCATTCTATCT 3-8-1-2-3 TTAtagccattCtaTCT 169_62 -21.25 5224 170ATTTAAATTTCCAAACATT 2-13-4 ATttaaatttccaaaCATT 170_1 -16.82 5427 171GCTAATTTAAATTTCC 4-10-2 GCTAatttaaatttCC 171_1 -18.50 5434 172ATCAATATCTTCTCAC 3-10-3 ATCaatatcttctCAC 172_1 -17.10 5785 173TATCAATATCTTCTCA 2-10-4 TAtcaatatcttCTCA 173_1 -17.55 5786 174CTACAAATTCAATTTACT 2-12-4 CTacaaattcaattTACT 174_1 -17.38 6341 175TCTTACTCTGACTTTCCA 2-14-2 TCttactctgactttcCA 175_1 -21.47 6694 176TCTTACTCTGACTTTCC 2-12-3 TCttactctgacttTCC 176_1 -21.53 6695 177AAATTTCCAAACCTTTC 2-11-4 AAatttccaaaccTTTC 177_1 -16.30 6958 178CTTCTTGTTTATCCCAA 2-11-4 CTtcttgtttatcCCAA 178_1 -22.77 7159 179TTCTTGTTTATCCCAA 2-10-4 TTcttgtttatcCCAA 179_1 -20.17 7159 180ATGCTTCTAACTAACA 4-10-2 ATGCttctaactaaCA 180_1 -19.21 7720 181CTTTAATGCTTCTAACT 4-11-2 CTTTaatgcttctaaCT 181_1 -18.49 7724 182CCTTTAATGCTTCTAAC 2-11-4 CCtttaatgcttcTAAC 182_1 -20.06 7725 183CTTTAATGCTTCTAAC 2-10-4 CTttaatgcttcTAAC 183_1 -16.07 7725 184TTCCTTTAATGCTTCTA 4-11-2 TTCCtttaatgcttcTA 184_1 -21.59 7727 185TATACCTTTCTTTAACCCT 2-15-2 TAtacctttctttaaccCT 185_1 -22.03 8117 186ATACCTTTCTTTAACCC 4-11-2 ATACctttctttaacCC 186_1 -22.68 8118 187TTATACCTTTCTTTAACC 4-12-2 TTATacctttctttaaCC 187_1 -21.52 8119 188TTTATACCTTTCTTTAAC 2-12-4 TTtatacctttcttTAAC 188_1 -17.01 8120 189TCAAGAATTCTCTCCTT 2-11-4 TCaagaattctctCCTT 189_1 -21.29 8571 190TTCAAGAATTCTCTCC 2-10-4 TTcaagaattctCTCC 190_1 -19.38 8573 191CTTCAAGAATTCTCTC 2-10-4 CTtcaagaattcTCTC 191_1 -18.00 8574 192TCTTCAAGAATTCTCT 2-10-4 TCttcaagaattCTCT 192_1 -18.46 8575 193ATCTTCAAGAATTCTC 3-10-3 ATCttcaagaattCTC 193_1 -17.04 8576 194TTTCTTACTATCTTCA 4-10-2 TTTCttactatcttCA 194_1 -17.47 8585 195CCTTTAGCATTTCTATT 2-11-4 CCtttagcatttcTATT 195_1 -21.72 8819 196TCCTTTAGCATTTCTAT 3-11-3 TCCtttagcatttcTAT 196_1 -22.39 8820 197GTTCTCTTTATTTCTTCT 2-12-4 GTtctctttatttcTTCT 197_1 -21.76 8887 198TTTACTGTCAACTCCT 2-10-4 TTtactgtcaacTCCT 198_1 -20.83 9150 199TTTCCAATGAATCTAT 2-10-4 TTtccaatgaatCTAT 199_1 -16.61 9201 200CCTTTCCAATGAATCTA 2-11-4 CCtttccaatgaaTCTA 200_1 -22.34 9202 201CTTTCCAATGAATCTA 2-10-4 CTttccaatgaaTCTA 201_1 -18.34 9202 202CCTTTCCAATGAATCT 3-10-3 CCTttccaatgaaTCT 202_1 -21.30 9203 203TTATACCCTTTCCAAT 2-10-4 TTataccctttcCAAT 203_1 -19.61 9209 204GTTTATACCCTTTCCAA 3-11-3 GTTtataccctttcCAA 204_1 -21.88 9210 205TTTATACCCTTTCCAA 2-10-4 TTtataccctttCCAA 205_1 -20.50 9210 206GTTTATACCCTTTCCA 2-11-3 GTttataccctttCCA 206_1 -22.69 9211 207TGTTTATACCCTTTCCA 3-12-2 TGTttataccctttcCA 207_1 -22.80 9211 208ACTGTTTATACCCTTTCC 2-14-2 ACtgtttataccctttCC 208_1 -22.96 9212 208ACTGTTTATACCCTTTCC 1-11-1-3-2 ActgtttataccCtttCC 208_2 -22.45 9212 208ACTGTTTATACCCTTTCC 1-2-1-10-1-1-2 ActGtttataccctTtCC 208_3 -22.17 9212208 ACTGTTTATACCCTTTCC 1-2-1-1-1-10-2 ActGtTtataccctttCC 208_4 -22.179212 208 ACTGTTTATACCCTTTCC 1-2-1-12-2 ActGtttataccctttCC 208_5 -21.879212 208 ACTGTTTATACCCTTTCC 1-3-1-11-2 ActgTttataccctttCC 208_6 -22.229212 208 ACTGTTTATACCCTTTCC 1-15-2 ActgtttataccctttCC 208_7 -21.56 9212209 ACTGTTTATACCCTTTC 4-11-2 ACTGtttatacccttTC 209_1 -21.65 9213 209ACTGTTTATACCCTTTC 1-11-1-2-2 ActgtttataccCttTC 209_2 -18.25 9213 209ACTGTTTATACCCTTTC 1-1-1-8-1-1-1-1-2 AcTgtttatacCcTtTC 209_3 -19.56 9213209 ACTGTTTATACCCTTTC 1-2-1-9-4 ActGtttatacccTTTC 209_4 -19.51 9213 209ACTGTTTATACCCTTTC 1-3-1-6-1-2-3 ActgTttatacCctTTC 209_5 -19.51 9213 209ACTGTTTATACCCTTTC 2-9-1-3-2 ACtgtttatacCcttTC 209_6 -19.43 9213 209ACTGTTTATACCCTTTC 1-2-1-7-1-3-2 ActGtttatacCcttTC 209_7 -18.35 9213 209ACTGTTTATACCCTTTC 1-3-1-8-1-1-2 ActgTttatacccTtTC 209_8 -18.53 9213 209ACTGTTTATACCCTTTC 1-11-1-1-3 ActgtttataccCtTTC 209_9 -19.06 9213 209ACTGTTTATACCCTTTC 2-10-1-2-2 ACtgtttataccCttTC 209_10 -19.64 9213 210AACTGTTTATACCCTTT 4-11-2 AACTgtttataccctTT 210_1 -19.51 9214 211TATGACTCCAATAATC 3-10-3 TATgactccaataATC 211_1 -16.57 10832 212CTCCTTTATGACTCCAA 4-11-2 CTCCtttatgactccAA 212_1 -22.74 10837 213CTCCTTTATGACTCCA 3-11-2 CTCctttatgactcCA 213_1 -21.50 10838 214CCATTATTTCTTAAATA 4-11-2 CCATtatttcttaaaTA 214_1 -17.56 10877 215ATTTCATATTACTAACTA 2-12-4 ATttcatattactaACTA 215_1 -16.64 11434 216CATTTCATATTACTAACT 3-12-3 CATttcatattactaACT 216_1 -17.70 11435 217TCATTTCATATTACTAAC 4-12-2 TCATttcatattactaAC 217_1 -16.72 11436 218ATCATTTCATATTACTA 3-11-3 ATCatttcatattaCTA 218_1 -17.23 11438 219TTATCATTTCATATTACT 4-12-2 TTATcatttcatattaCT 219_1 -17.77 11439 220TGTACTTTCCTTTACCA 2-13-2 TGtactttcctttacCA 220_1 -20.37 11464 221TATACACCATCATTATA 4-11-2 TATAcaccatcattaTA 221_1 -18.48 11507 222TTATACACCATCATTAT 3-11-3 TTAtacaccatcatTAT 222_1 -17.83 11508 223TATTTATACACCATCAT 3-11-3 TATttatacaccatCAT 223_1 -18.54 11511 224TTATTTATACACCATC 2-10-4 TTatttatacacCATC 224_1 -16.60 11513 225AATTATTTATACACCAT 2-11-4 AAttatttatacaCCAT 225_1 -16.82 11514 226CATGACACTTACATAA 3-10-3 CATgacacttacaTAA 226_1 -16.26 11736 227AGTTCACTACTATTAC 3-10-3 AGTtcactactatTAC 227_1 -17.55 12361 228ATAAGCTTACCTCATA 2-10-4 ATaagcttacctCATA 228_1 -19.32 12794 229TATAAGCTTACCTCAT 3-10-3 TATaagcttacctCAT 229_1 -19.32 12795 230ATATAAGCTTACCTCA 4-10-2 ATATaagcttacctCA 230_1 -19.32 12796 231CTTCCCTTTGATAACAT 3-11-3 CTTccctttgataaCAT 231_1 -21.19 12894 232TTCCCTTTGATAACAT 4-10-2 TTCCctttgataacAT 232_1 -19.27 12894 233CCTTCCCTTTGATAACA 2-12-3 CCttccctttgataACA 233_1 -23.06 12895 234CTTCCCTTTGATAACA 4-10-2 CTTCcctttgataaCA 234_1 -20.51 12895 235CCTTCCCTTTGATAAC 3-11-2 CCTtccctttgataAC 235_1 -20.96 12896 236TTGATTCAATTCCCTTA 2-11-4 TTgattcaattccCTTA 236_1 -20.48 13223 236TTGATTCAATTCCCTTA 2-9-1-1-1-1-2 TTgattcaattCcCtTA 236_2 -19.54 13223 236TTGATTCAATTCCCTTA 2-10-1-1-3 TTgattcaattcCcTTA 236_3 -19.59 13223 236TTGATTCAATTCCCTTA 2-1-1-8-1-2-2 TTgAttcaattcCctTA 236_4 -19.06 13223 236TTGATTCAATTCCCTTA 2-2-1-7-1-2-2 TTgaTtcaattcCctTA 236_5 -19.00 13223 236TTGATTCAATTCCCTTA 2-9-1-3-2 TTgattcaattCcctTA 236_6 -18.65 13223 236TTGATTCAATTCCCTTA 1-2-2-6-2-2-2 TtgATtcaattCCctTA 236_7 -21.37 13223 236TTGATTCAATTCCCTTA 2-1-1-7-1-1-1-1-2 TTgAttcaattCcCtTA 236_8 -20.04 13223236 TTGATTCAATTCCCTTA 1-1-2-7-1-1-1-1-2 TtGAttcaattCcCtTA 236_9 -20.1013223 236 TTGATTCAATTCCCTTA 1-2-1-9-4 TtgAttcaattccCTTA 236_10 -19.6713223 236 TTGATTCAATTCCCTTA 1-3-1-6-1-1-1-1-2 TtgaTtcaattCcCtTA 236_11-18.67 13223 236 TTGATTCAATTCCCTTA 2-10-1-2-2 TTgattcaattcCctTA 236_12-18.56 13223 236 TTGATTCAATTCCCTTA 1-2-2-7-2-1-2 TtgATtcaattcCCtTA236_13 -21.49 13223 236 TTGATTCAATTCCCTTA 1-1-2-8-1-2-2TtGAttcaattcCctTA 236_14 -19.13 13223 236 TTGATTCAATTCCCTTA 2-11-1-1-2TTgattcaattccCtTA 236_15 -18.77 13223 236 TTGATTCAATTCCCTTA1-1-1-1-1-8-1-1-2 TtGaTtcaattccCtTA 236_16 -18.07 13223 236TTGATTCAATTCCCTTA 1-1-2-7-2-2-2 TtGAttcaattCCctTA 236_17 -21.50 13223236 TTGATTCAATTCCCTTA 1-2-1-7-1-1-4 TtgAttcaattCcCTTA 236_18 -20.4413223 236 TTGATTCAATTCCCTTA 3-8-1-1-1-1-2 TTGattcaattCcCtTA 236_19-20.60 13223 236 TTGATTCAATTCCCTTA 2-2-1-6-1-3-2 TTgaTtcaattCcctTA236_20 -19.09 13223 236 TTGATTCAATTCCCTTA 2-2-1-7-2-1-2TTgaTtcaattcCCtTA 236_21 -21.49 13223 237 ATTGATTCAATTCCCTT 2-11-4ATtgattcaattcCCTT 237_1 -21.28 13224 237 ATTGATTCAATTCCCTT 3-8-3-1-2ATTgattcaatTCCcTT 237_2 -22.78 13224 237 ATTGATTCAATTCCCTT 1-1-1-8-3-1-2AtTgattcaatTCCcTT 237_3 -21.02 13224 237 ATTGATTCAATTCCCTT 1-2-1-8-2-1-2AttGattcaattCCcTT 237_4 -19.40 13224 237 ATTGATTCAATTCCCTT 1-3-1-7-2-1-2AttgAttcaattCCcTT 237_5 -19.74 13224 237 ATTGATTCAATTCCCTT 1-2-1-7-2-1-3AttGattcaatTCcCTT 237_6 -19.67 13224 237 ATTGATTCAATTCCCTT 2-2-1-7-1-1-3ATtgAttcaattCcCTT 237_7 -20.27 13224 237 ATTGATTCAATTCCCTT 1-1-1-9-1-1-3AtTgattcaattCcCTT 237_8 -19.32 13224 237 ATTGATTCAATTCCCTT 1-3-1-7-1-1-3AttgAttcaattCcCTT 237_9 -19.02 13224 237 ATTGATTCAATTCCCTT1-1-1-1-1-7-2-1-2 AtTgAttcaattCCcTT 237_10 -20.53 13224 237ATTGATTCAATTCCCTT 1-2-2-7-2-1-2 AttGAttcaattCCcTT 237_11 -21.11 13224237 ATTGATTCAATTCCCTT 1-2-1-8-1-1-3 AttGattcaattCcCTT 237_12 -18.6813224 237 ATTGATTCAATTCCCTT 1-1-2-8-1-2-2 AtTGattcaattCccTT 237_13-18.81 13224 237 ATTGATTCAATTCCCTT 3-10-1-1-2 ATTgattcaattcCcTT 237_14-19.42 13224 237 ATTGATTCAATTCCCTT 1-1-2-9-4 AtTGattcaattcCCTT 237_15-21.89 13224 237 ATTGATTCAATTCCCTT 2-2-1-8-1-1-2 ATtgAttcaattcCcTT237_16 -18.61 13224 237 ATTGATTCAATTCCCTT 1-2-2-6-3-1-2AttGAttcaatTCCcTT 237_17 -22.09 13224 237 ATTGATTCAATTCCCTT1-1-1-8-2-1-3 AtTgattcaatTCcCTT 237_18 -20.30 13224 237ATTGATTCAATTCCCTT 1-1-1-9-2-1-2 AtTgattcaattCCcTT 237_19 -20.03 13224237 ATTGATTCAATTCCCTT 1-1-1-1-1-7-1-1-3 AtTgAttcaattCcCTT 237_20 -19.8213224 237 ATTGATTCAATTCCCTT 3-1-1-8-1-1-2 ATTgAttcaattcCcTT 237_21-19.92 13224 238 TTGATTCAATTCCCTT 2-10-4 TTgattcaattcCCTT 238_1 -20.5213224 239 TATTGATTCAATTCCCT 2-11-4 TAttgattcaattCCCT 239_1 -22.82 13225239 TATTGATTCAATTCCCT 3-9-2-1-2 TATtgattcaatTCcCT 239_2 -21.17 13225 239TATTGATTCAATTCCCT 2-9-1-1-1-1-2 TAttgattcaaTtCcCT 239_3 -19.37 13225 239TATTGATTCAATTCCCT 1-1-2-7-3-1-2 TaTTgattcaaTTCcCT 239_4 -21.49 13225 239TATTGATTCAATTCCCT 1-3-1-6-3-1-2 TattGattcaaTTCcCT 239_5 -19.90 13225 239TATTGATTCAATTCCCT 2-9-1-2-3 TAttgattcaaTtcCCT 239_6 -20.89 13225 239TATTGATTCAATTCCCT 1-10-1-2-3 TattgattcaaTtcCCT 239_7 -19.76 13225 239TATTGATTCAATTCCCT 1-1-1-1-1-8-1-1-2 TaTtGattcaattCcCT 239_8 -18.41 13225239 TATTGATTCAATTCCCT 1-2-2-8-1-1-2 TatTGattcaattCcCT 239_9 -19.66 13225239 TATTGATTCAATTCCCT 1-2-1-9-1-1-2 TatTgattcaattCcCT 239_10 -18.6013225 239 TATTGATTCAATTCCCT 2-2-1-10-2 TAttGattcaattccCT 239_11 -18.3313225 239 TATTGATTCAATTCCCT 1-12-4 TattgattcaattCCCT 239_12 -21.69 13225239 TATTGATTCAATTCCCT 2-1-1-9-1-1-2 TAtTgattcaattCcCT 239_13 -19.7313225 239 TATTGATTCAATTCCCT 2-12-3 TAttgattcaattcCCT 239_14 -20.45 13225239 TATTGATTCAATTCCCT 1-2-1-10-3 TatTgattcaattcCCT 239_15 -20.11 13225239 TATTGATTCAATTCCCT 1-1-3-10-2 TaTTGattcaattccCT 239_16 -19.84 13225239 TATTGATTCAATTCCCT 1-1-1-1-1-6-3-1-2 TaTtGattcaaTTCcCT 239_17 -20.3413225 239 TATTGATTCAATTCCCT 2-2-1-6-1-1-1-1-2 TAttGattcaaTtCcCT 239_18-19.54 13225 239 TATTGATTCAATTCCCT 2-1-1-8-2-1-2 TAtTgattcaatTCcCT239_19 -20.72 13225 239 TATTGATTCAATTCCCT 1-1-2-9-1-1-2TaTTgattcaattCcCT 239_20 -19.55 13225 239 TATTGATTCAATTCCCT 2-1-1-10-3TAtTgattcaattcCCT 239_21 -21.24 13225 240 TATTGATTCAATTCCC 3-10-3TATtgattcaattCCC 240_1 -20.58 13226 241 GCACATTCTTTCTATAC 3-11-3GCAcattctttctaTAC 241_1 -21.17 15115 241 GCACATTCTTTCTATAC 1-1-3-6-2-2-2GcACAttctttCTatAC 241_2 -20.68 15115 241 GCACATTCTTTCTATAC1-1-1-1-1-6-1-2-3 GcAcAttctttCtaTAC 241_3 -18.46 15115 241GCACATTCTTTCTATAC 1-1-2-7-1-2-3 GcACattctttCtaTAC 241_4 -19.49 15115 241GCACATTCTTTCTATAC 2-9-1-3-2 GCacattctttCtatAC 241_5 -18.68 15115 241GCACATTCTTTCTATAC 1-1-3-8-4 GcACAttctttctATAC 241_6 -20.89 15115 241GCACATTCTTTCTATAC 2-2-1-9-3 GCacAttctttctaTAC 241_7 -19.66 15115 241GCACATTCTTTCTATAC 2-1-1-11-2 GCaCattctttctatAC 241_8 -18.39 15115 241GCACATTCTTTCTATAC 1-1-3-9-3 GcACAttctttctaTAC 241_9 -19.98 15115 241GCACATTCTTTCTATAC 3-12-2 GCAcattctttctatAC 241_10 -19.27 15115 241GCACATTCTTTCTATAC 1-1-1-1-1-6-1-1-4 GcAcAttctttCtATAC 241_11 -19.3615115 241 GCACATTCTTTCTATAC 3-8-1-1-1-1-2 GCAcattctttCtAtAC 241_12-20.34 15115 241 GCACATTCTTTCTATAC 2-1-1-7-1-2-3 GCaCattctttCtaTAC241_13 -21.27 15115 241 GCACATTCTTTCTATAC 1-2-2-8-4 GcaCAttctttctATAC241_14 -20.33 15115 241 GCACATTCTTTCTATAC 1-1-3-10-2 GcACAttctttctatAC241_15 -18.08 15115 242 GAATTTCAACTACTAT 2-10-4 GAatttcaactaCTAT 242_1-16.13 15258 243 CCATTTATTTCCATTTAT 3-12-3 CCAtttatttccattTAT 243_1-21.92 15568 244 TTTCCATTTATTTCCATTT 4-13-2 TTTCcatttatttccatTT 244_1-20.93 15570 244 TTTCCATTTATTTCCATTT 1-4-1-7-1-1-4 TttccAtttatttCcATTT244_2 -20.48 15570 244 TTTCCATTTATTTCCATTT 2-1-1-10-2-1-2TTtCcatttatttcCAtTT 244_3 -21.47 15570 244 TTTCCATTTATTTCCATTT1-2-1-1-1-7-1-3-2 TttCcAtttatttCcatTT 244_4 -19.43 15570 244TTTCCATTTATTTCCATTT 2-2-2-11-2 TTtcCAtttatttccatTT 244_5 -20.70 15570245 CTTTCCATTTATTTCCAT 3-12-3 CTTtccatttatttcCAT 245_1 -22.31 15572 246TCTTTCCATTTATTTCCA 4-12-2 TCTTtccatttatttcCA 246_1 -22.74 15573 247ATCTTTCCATTTATTTCC 3-12-3 ATCtttccatttattTCC 247_1 -22.85 15574 248TTCCATGCAAACTTTA 4-10-2 TTCCatgcaaacttTA 248_1 -19.01 15722 249CAGTTTAAATTCACAC 3-10-3 CAGtttaaattcaCAC 249_1 -16.68 16597 250CTATTCCAGTTTAAAT 4-10-2 CTATtccagtttaaAT 250_1 -16.86 16603 251TGCAAATACCTCTTCA 4-10-2 TGCAaatacctcttCA 251_1 -21.49 16730 252CTAAATAGATTCCACT 2-10-4 CTaaatagattcCACT 252_1 -17.95 16849 253TATTGATATTTACTCT 2-10-4 TAttgatatttaCTCT 253_1 -16.32 17089 254CCTTAGTATTACAATT 4-10-2 CCTTagtattacaaTT 254_1 -17.43 17401 255CTATTCAATAAACTAAACA 4-13-2 CTATtcaataaactaaaCA 255_1 -16.45 24290 256CAGCTATTCAATAAAC 4-10-2 CAGCtattcaataaAC 256_1 -16.94 24296 257TATAGACCCAAACTAT 3-10-3 TATagacccaaacTAT 257_1 -18.15 24811 258TAATCCCATACATCTAT 2-11-4 TAatcccatacatCTAT 258_1 -20.45 25032 259ATAATCCCATACATCTA 3-11-3 ATAatcccatacatCTA 259_1 -20.45 25033 260ATCTCAACTACCATTT 4-10-2 ATCTcaactaccatTT 260_1 -18.14 25250 261AATCTCAACTACCATT 4-10-2 AATCtcaactaccaTT 261_1 -16.76 25251 262ACAACTTCTATCATAC 3-10-3 ACAacttctatcaTAC 262_1 -16.33 25718 263GAACAACTTCTATCAT 2-10-4 GAacaacttctaTCAT 263_1 -16.94 25720 264TGAACAACTTCTATCA 3-10-3 TGAacaacttctaTCA 264_1 -17.36 25721 265TACACAAATACTTAAATCA 4-13-2 TACAcaaatacttaaatCA 265_1 -16.93 26331 266TTAAGCTTTCACCTAT 2-10-4 TTaagctttcacCTAT 266_1 -19.36 27165 267AAACTCTTGCATCTACT 2-13-2 AAactcttgcatctaCT 267_1 -16.65 27248 268AAATTTCTCAACCTAAATTT 2-14-4 AAatttctcaacctaaATTT 268_1 -16.78 29330 269CCAACATAGATCCTCT 2-10-4 CCaacatagatcCTCT 269_1 -22.49 29635 270TCCAACATAGATCCTCT 2-11-4 TCcaacatagatcCTCT 270_1 -22.81 29635 271CTCCAACATAGATCCTC 3-11-3 CTCcaacatagatcCTC 271_1 -22.81 29636 272TCCAACATAGATCCTC 2-10-4 TCcaacatagatCCTC 272_1 -21.69 29636 273CTCCAACATAGATCCT 3-10-3 CTCcaacatagatCCT 273_1 -22.68 29637 274TCTCCAACATAGATCCT 4-11-2 TCTCcaacatagatcCT 274_1 -22.81 29637 275ATTCTCAATTGCACTT 4-10-2 ATTCtcaattgcacTT 275_1 -17.90 29661 276TATTCTCAATTGCACTT 4-11-2 TATTctcaattgcacTT 276_1 -18.54 29661 277TCACCTAATAGCACCA 2-10-4 TCacctaatagcACCA 277_1 -21.99 29684 278TTCACCTAATAGCACCA 2-11-4 TTcacctaatagcACCA 278_1 -22.53 29684 279CATTATTATTTAACCTT 2-11-4 CAttattatttaaCCTT 279_1 -17.83 30455 280ACATTATTATTTAACCT 3-11-3 ACAttattatttaaCCT 280_1 -18.05 30456 281TACATTATTATTTAACC 4-11-2 TACAttattatttaaCC 281_1 -16.80 30457 282CATTTACATTATTATTTAAC 2-14-4 CAtttacattattattTAAC 282_1 -16.44 30458 283CTCATTTACATTATTATT 4-12-2 CTCAtttacattattaTT 283_1 -17.33 30462 284TATCTCATTTACATTATT 4-12-2 TATCtcatttacattaTT 284_1 -17.62 30465 285ATCATTCTCAACAATTA 4-11-2 ATCAttctcaacaatTA 285_1 -17.04 30601 285ATCATTCTCAACAATTA 4-7-6 ATCAttctcaaCAATTA 285_2 -21.48 30601 285ATCATTCTCAACAATTA 1-1-3-6-6 AtCATtctcaaCAATTA 285_3 -20.80 30601 285ATCATTCTCAACAATTA 5-6-2-2-2 ATCATtctcaaCAatTA 285_4 -20.46 30601 285ATCATTCTCAACAATTA 4-7-1-1-4 ATCAttctcaaCaATTA 285_5 -19.80 30601 285ATCATTCTCAACAATTA 5-7-1-1-3 ATCATtctcaacAaTTA 285_6 -19.31 30601 285ATCATTCTCAACAATTA 5-6-3-1-2 ATCATtctcaaCAAtTA 285_7 -20.97 30601 285ATCATTCTCAACAATTA 4-7-2-1-3 ATCAttctcaaCAaTTA 285_8 -20.16 30601 285ATCATTCTCAACAATTA 5-6-1-1-4 ATCATtctcaaCaATTA 285_9 -21.05 30601 285ATCATTCTCAACAATTA 5-6-1-1-1-1-2 ATCATtctcaaCaAtTA 285_10 -19.29 30601285 ATCATTCTCAACAATTA 1-1-3-7-5 AtCATtctcaacAATTA 285_11 -18.70 30601286 AAGATCATTCTCAACA 4-10-2 AAGAtcattctcaaCA 286_1 -17.15 30605 287TCTCAAAGATCATTCTC 3-11-3 TCTcaaagatcattCTC 287_1 -19.02 30609 288TCTCAAAGATCATTCT 4-10-2 TCTCaaagatcattCT 288_1 -17.81 30610 289ACTTAATTATACTTCC 4-10-2 ACTTaattatacttCC 289_1 -17.28 30667 290TACACTTAATTATACTTC 2-12-4 TAcacttaattataCTTC 290_1 -16.87 30668 291TTACACTTAATTATACTT 3-12-3 TTAcacttaattataCTT 291_1 -16.20 30669 292TTTACACTTAATTATACT 2-12-4 TTtacacttaattaTACT 292_1 -16.23 30670 293CTATTTAATTTACACTT 3-11-3 CTAtttaatttacaCTT 293_1 -16.26 30679 294TATCTATTTAATTTACAC 3-12-3 TATctatttaatttaCAC 294_1 -16.06 30681 295TTTATCTATTTAATTTACA 4-13-2 TTTAtctatttaatttaCA 295_1 -16.34 30682 296CTCTGCTTATAACTTT 4-10-2 CTCTgcttataactTT 296_1 -18.51 30699 297CCTCTGCTTATAACTT 3-10-3 CCTctgcttataaCTT 297_1 -21.29 30700 298TCCTCTGCTTATAACTT 3-12-2 TCCtctgcttataacTT 298_1 -20.86 30700 299TCCTCTGCTTATAACT 3-11-2 TCCtctgcttataaCT 299_1 -20.70 30701 300TTCCTCTGCTTATAACT 3-12-2 TTCctctgcttataaCT 300_1 -20.03 30701 301TTTCCTCTGCTTATAAC 4-11-2 TTTCctctgcttataAC 301_1 -19.20 30702 302TACTATACTTTCCTCT 2-10-4 TActatactttcCTCT 302_1 -20.07 30711 303TTCTACTATACTTTCC 4-10-2 TTCTactatactttCC 303_1 -19.55 30714 304AGTTCTACTATACTTTC 4-11-2 AGTTctactatacttTC 304_1 -18.49 30715 304AGTTCTACTATACTTTC 1-10-6 AgttctactatACTTTC 304_2 -18.76 30715 304AGTTCTACTATACTTTC 1-1-2-7-1-1-4 AgTTctactatAcTTTC 304_3 -18.23 30715 304AGTTCTACTATACTTTC 3-8-2-2-2 AGTtctactatACttTC 304_4 -19.19 30715 304AGTTCTACTATACTTTC 2-2-1-6-1-1-4 AGttCtactatAcTTTC 304_5 -19.07 30715 304AGTTCTACTATACTTTC 1-2-2-8-4 AgtTCtactatacTTTC 304_6 -18.46 30715 304AGTTCTACTATACTTTC 3-10-1-1-2 AGTtctactatacTtTC 304_7 -18.12 30715 304AGTTCTACTATACTTTC 3-11-3 AGTtctactatactTTC 304_8 -18.42 30715 304AGTTCTACTATACTTTC 3-1-1-10-2 AGTtCtactatacttTC 304_9 -18.58 30715 304AGTTCTACTATACTTTC 2-1-2-10-2 AGtTCtactatacttTC 304_10 -18.02 30715 304AGTTCTACTATACTTTC 1-2-2-6-2-1-3 AgtTCtactatACtTTC 304_11 -19.02 30715304 AGTTCTACTATACTTTC 2-1-2-6-1-3-2 AGtTCtactatActtTC 304_12 -18.2230715 304 AGTTCTACTATACTTTC 2-2-1-7-2-1-2 AGttCtactataCTtTC 304_13-19.22 30715 304 AGTTCTACTATACTTTC 3-1-1-7-1-1-3 AGTtCtactataCtTTC304_14 -20.39 30715 304 AGTTCTACTATACTTTC 1-1-1-1-1-8-4AgTtCtactatacTTTC 304_15 -18.13 30715 305 GTTCTACTATACTTTC 4-10-2GTTCtactatacttTC 305_1 -17.48 30715 306 CATTATATTTAAACTATCA 4-13-2CATTatatttaaactatCA 306_1 -16.93 31630 307 CACATTATATTTAAACTAT 2-13-4CAcattatatttaaaCTAT 307_1 -17.11 31632 308 ACACATTATATTTAAACTA 3-13-3ACAcattatatttaaaCTA 308_1 -17.09 31633 309 ACCACCTAAGACCTCAA 2-11-4ACcacctaagaccTCAA 309_1 -22.49 32755 310 CCACCTAAGACCTCAA 2-10-4CCacctaagaccTCAA 310_1 -22.63 32755 311 ACCACCTAAGACCTCA 2-11-3ACcacctaagaccTCA 311_1 -21.74 32756 312 ACCTTAAGTAACATTT 4-10-2ACCTtaagtaacatTT 312_1 -16.82 33366 313 CACCTTAAGTAACATT 4-10-2CACCttaagtaacaTT 313_1 -18.05 33367 314 CCACCTTAAGTAACAT 3-10-3CCAccttaagtaaCAT 314_1 -20.70 33368 315 ACCACCTTAAGTAACA 4-10-2ACCAccttaagtaaCA 315_1 -20.68 33369 316 TTATTAACCACCTTAA 3-10-3TTAttaaccacctTAA 316_1 -16.19 33375 317 CATTATTAACCACCTT 2-10-4CAttattaaccaCCTT 317_1 -19.92 33377 318 ACATTATTAACCACCT 3-10-3ACAttattaaccaCCT 318_1 -20.14 33378 319 ACCAATTATACTTACAA 3-11-3ACCaattatacttaCAA 319_1 -17.16 36606 320 AACCAATTATACTTACA 4-11-2AACCaattatacttaCA 320_1 -17.16 36607 321 CAAATACAGATTATCC 2-10-4CAaatacagattATCC 321_1 -16.44 38092 322 TTTACATTCCCATCATC 2-11-4TTtacattcccatCATC 322_1 -21.08 38297 323 CACACCTATTATATAAT 4-11-2CACAcctattatataAT 323_1 -17.02 39173 324 TCACACCTATTATATAA 3-11-3TCAcacctattataTAA 324_1 -17.02 39174 325 CTTCACACCTATTATATA 2-12-4CTtcacacctattaTATA 325_1 -20.65 39175 326 ACTTCACACCTATTATAT 3-12-3ACTtcacacctattaTAT 326_1 -20.46 39176 327 GCTCACACTAATTATT 2-10-4GCtcacactaatTATT 327_1 -18.72 39228 328 ATGCTCACACTAATTA 4-10-2ATGCtcacactaatTA 328_1 -19.38 39230 329 AATGCTCACACTAATT 4-10-2AATGctcacactaaTT 329_1 -16.21 39231 330 AAACTGTACACCTACT 2-10-4AAactgtacaccTACT 330_1 -17.99 39563 331 GTTTCCATCTACTATTA 2-11-4GTttccatctactATTA 331_1 -19.78 39808 332 TTTCCATCTACTATTA 4-10-2TTTCcatctactatTA 332_1 -17.25 39808 333 TGACATAACCATATAC 3-10-3TGAcataaccataTAC 333_1 -16.63 39931 334 GCTCCCAAACAACTAA 2-12-2GCtcccaaacaactAA 334_1 -17.55 41114 335 CCTCAATACTCTACTT 4-10-2CCTCaatactctacTT 335_1 -20.30 41444 336 GACCTCAATACTCTACT 3-11-3GACctcaatactctACT 336_1 -21.01 41445 337 GACCTCAATACTCTAC 4-10-2GACCtcaatactctAC 337_1 -20.02 41446 338 TACTAAACATACACATA 4-11-2TACTaaacatacacaTA 338_1 -16.12 41725 339 CTACTAAACATACACAT 3-11-3CTActaaacatacaCAT 339_1 -17.31 41726 340 TTCTACTAAACATACAC 3-11-3TTCtactaaacataCAC 340_1 -16.07 41728 341 TACCAATAGTTACCTT 2-10-4TAccaatagttaCCTT 341_1 -20.03 42167 342 CTTACCAATAGTTACCT 3-11-3CTTaccaatagttaCCT 342_1 -22.29 42168 343 TTACCAATAGTTACCT 3-10-3TTAccaatagttaCCT 343_1 -20.03 42168 344 CTTACCAATAGTTACC 4-10-2CTTAccaatagttaCC 344_1 -20.03 42169 345 TCTTACCAATAGTTACC 4-11-2TCTTaccaatagttaCC 345_1 -21.30 42169 346 TCAAAGCACACCACCAC 2-12-3TCaaagcacaccacCAC 346_1 -21.69 42287 347 ATTCAAAGCACACCACC 2-12-3ATtcaaagcacaccACC 347_1 -21.00 42289 348 AGACTAATCCTCTTAA 3-10-3AGActaatcctctTAA 348_1 -17.72 43452 349 TAGACTAATCCTCTTA 4-10-2TAGActaatcctctTA 349_1 -19.20 43453 350 CCCATTTCTAACATTTAC 3-12-3CCCatttctaacattTAC 350_1 -22.93 43562 351 ACCCATTTCTAACATT 4-10-2ACCCatttctaacaTT 351_1 -20.64 43565 352 AACCCATTTCTAACAT 4-10-2AACCcatttctaacAT 352_1 -18.25 43566 353 CCTCAACTTCACCAAT 2-10-4CCtcaacttcacCAAT 353_1 -21.73 43634 354 ACTGATTTCCTTAAAC 4-10-2ACTGatttccttaaAC 354_1 -16.67 44180 355 CACTGATTTCCTTAAAC 4-11-2CACTgatttccttaaAC 355_1 -18.91 44180 356 CCACTGATTTCCTTAAA 4-11-2CCACtgatttccttaAA 356_1 -20.91 44181 357 ACCACTGATTTCCTTA 2-10-4ACcactgatttcCTTA 357_1 -20.98 44183 358 CACCACTGATTTCCTT 3-10-3CACcactgatttcCTT 358_1 -22.04 44184 359 CTCTGCAATACACCAA 2-10-4CTctgcaatacaCCAA 359_1 -20.90 44439 360 ACTCTGCAATACACCA 3-10-3ACTctgcaatacaCCA 360_1 -22.19 44440 361 TACTCTGCAATACACCA 2-11-4TActctgcaatacACCA 361_1 -22.32 44440 361 TACTCTGCAATACACCA1-1-1-10-1-1-2 TaCtctgcaatacAcCA 361_2 -19.29 44440 361TACTCTGCAATACACCA 1-3-1-8-1-1-2 TactCtgcaatacAcCA 361_3 -19.28 44440 361TACTCTGCAATACACCA 1-10-1-3-2 TactctgcaatAcacCA 361_4 -18.35 44440 361TACTCTGCAATACACCA 2-10-2-1-2 TActctgcaataCAcCA 361_5 -21.63 44440 361TACTCTGCAATACACCA 1-13-3 TactctgcaatacaCCA 361_6 -20.54 44440 361TACTCTGCAATACACCA 2-10-1-2-2 TActctgcaataCacCA 361_7 -20.06 44440 361TACTCTGCAATACACCA 1-1-1-12-2 TaCtctgcaatacacCA 361_8 -19.14 44440 361TACTCTGCAATACACCA 1-2-2-10-2 TacTCtgcaatacacCA 361_9 -20.33 44440 361TACTCTGCAATACACCA 1-3-1-10-2 TactCtgcaatacacCA 361_10 -19.13 44440 362TACTCTGCAATACACC 2-10-4 TActctgcaataCACC 362_1 -21.12 44441 362TACTCTGCAATACACC 1-1-1-11-2 TaCtctgcaatacaCC 362_2 -18.23 44441 362TACTCTGCAATACACC 1-1-1-10-3 TaCtctgcaatacACC 362_3 -18.78 44441 362TACTCTGCAATACACC 1-3-1-7-4 TactCtgcaataCACC 362_4 -20.87 44441 362TACTCTGCAATACACC 3-11-2 TACtctgcaatacaCC 362_5 -19.86 44441 362TACTCTGCAATACACC 2-2-1-9-2 TActCtgcaatacaCC 362_6 -19.44 44441 362TACTCTGCAATACACC 2-12-2 TActctgcaatacaCC 362_7 -18.47 44441 362TACTCTGCAATACACC 1-2-2-9-2 TacTCtgcaatacaCC 362_8 -19.42 44441 362TACTCTGCAATACACC 2-1-2-9-2 TAcTCtgcaatacaCC 362_9 -20.64 44441 362TACTCTGCAATACACC 1-3-1-9-2 TactCtgcaatacaCC 362_10 -18.22 44441 363TTACTCTGCAATACACC 2-11-4 TTactctgcaataCACC 363_1 -21.71 44441 364TTACTCTGCAATACAC 3-10-3 TTActctgcaataCAC 364_1 -17.75 44442 365TTTACTCTGCAATACAC 3-11-3 TTTactctgcaataCAC 365_1 -18.34 44442 366CTTTACTCTGCAATACA 2-11-4 CTttactctgcaaTACA 366_1 -20.23 44443 367TTTACTCTGCAATACA 2-10-4 TTtactctgcaaTACA 367_1 -17.56 44443 368GACCACACTTTCTACCA 2-13-2 GAccacactttctacCA 368_1 -21.72 44477 369GACCACACTTTCTACC 2-12-2 GAccacactttctaCC 369_1 -20.81 44478 370AAGAAACACCCTTCCA 2-10-4 AAgaaacaccctTCCA 370_1 -21.48 44776 371ATCTGCTACATATTCTT 4-11-2 ATCTgctacatattcTT 371_1 -19.88 45216 372ATCTGCTACATATTCT 4-10-2 ATCTgctacatattCT 372_1 -19.71 45217 373CATCTGCTACATATTCT 4-11-2 CATCtgctacatattCT 373_1 -21.32 45217 374CATCTGCTACATATTC 4-10-2 CATCtgctacatatTC 374_1 -18.82 45218 375TTCAACCCTAATCACT 4-10-2 TTCAaccctaatcaCT 375_1 -19.99 45246 376ATTCAACCCTAATCAC 2-10-4 ATtcaaccctaaTCAC 376_1 -18.67 45247 377CATTCAACCCTAATCA 3-10-3 CATtcaaccctaaTCA 377_1 -19.93 45248 378GCATTCAACCCTAATCA 3-12-2 GCAttcaaccctaatCA 378_1 -22.56 45248 379AGCATTCAACCCTAATC 4-11-2 AGCAttcaaccctaaTC 379_1 -22.98 45249 380GCATTCAACCCTAATC 4-10-2 GCATtcaaccctaaTC 380_1 -21.63 45249 381AGCATTCAACCCTAAT 4-10-2 AGCAttcaaccctaAT 381_1 -21.62 45250 382CAGCATTCAACCCTAAT 3-12-2 CAGcattcaaccctaAT 382_1 -21.12 45250 383TTAAATCCAGCATTCA 3-10-3 TTAaatccagcatTCA 383_1 -18.08 45258 384CTCCATATTTAAATCC 4-10-2 CTCCatatttaaatCC 384_1 -20.02 45266 385GCTCCATATTTAAATCC 4-11-2 GCTCcatatttaaatCC 385_1 -22.84 45266 386GCTCCATATTTAAATC 4-10-2 GCTCcatatttaaaTC 386_1 -18.78 45267 387AGCTCCATATTTAAAT 4-10-2 AGCTccatatttaaAT 387_1 -18.62 45268 388TAAGCTCCATATTTAA 3-10-3 TAAgctccatattTAA 388_1 -16.08 45270 389CCTAAGCTCCATATTTA 3-11-3 CCTaagctccatatTTA 389_1 -22.65 45271 390CTAAGCTCCATATTTA 4-10-2 CTAAgctccatattTA 390_1 -18.81 45271 391CCTAAGCTCCATATTT 4-10-2 CCTAagctccatatTT 391_1 -21.57 45272 392TCTACCCTAAATTCCC 2-11-3 TCtaccctaaattCCC 392_1 -23.00 45560 393CACATCTTGTATACAA 3-10-3 CACatcttgtataCAA 393_1 -16.65 45627 394ACACATCTTGTATACA 4-10-2 ACACatcttgtataCA 394_1 -17.95 45628 395CTACACATCTTGTATAC 3-11-3 CTAcacatcttgtaTAC 395_1 -19.13 45629 396TACACATCTTGTATAC 3-10-3 TACacatcttgtaTAC 396_1 -16.73 45629 397CTTGACTACACATCTT 3-10-3 CTTgactacacatCTT 397_1 -18.89 45635 398CTCTACAACAGTCCCA 3-11-2 CTCtacaacagtccCA 398_1 -22.06 45709 399TCTCTACAACAGTCCCA 2-13-2 TCtctacaacagtccCA 399_1 -21.70 45709 400ATAACATTACTCTTAACA 3-12-3 ATAacattactcttaACA 400_1 -17.03 46215 401TTTGACATTCCATCTCC 2-12-3 TTtgacattccatcTCC 401_1 -21.62 46256 402CTTTGACATTCCATCTC 2-11-4 CTttgacattccaTCTC 402_1 -21.88 46257 403TCTTTGACATTCCATCTC 4-12-2 TCTTtgacattccatcTC 403_1 -22.41 46257 404TTTGACATTCCATCTC 3-10-3 TTTgacattccatCTC 404_1 -19.40 46257 405ATCTTTGACATTCCATC 2-11-4 ATctttgacattcCATC 405_1 -20.53 46259 406TATCTTTGACATTCCAT 2-11-4 TAtctttgacattCCAT 406_1 -21.32 46260 407TACTATCTTTGACATTC 4-11-2 TACTatctttgacatTC 407_1 -18.39 46263 408TACTATCTTTGACATT 4-10-2 TACTatctttgacaTT 408_1 -16.84 46264 409CTGTATACACCATCCC 2-12-2 CTgtatacaccatcCC 409_1 -21.84 46392 410TCTGTATACACCATCC 4-10-2 TCTGtatacaccatCC 410_1 -22.73 46393 411TTTCTGACTCCCTATCC 2-13-2 TTtctgactccctatCC 411_1 -22.48 46420 412CCTATGTTAATACTTTC 4-11-2 CCTAtgttaatacttTC 412_1 -19.53 46505 413CTATGTTAATACTTTC 4-10-2 CTATgttaatacttTC 413_1 -16.09 46505 414CCTATGTTAATACTTT 4-10-2 CCTAtgttaatactTT 414_1 -17.85 46506 415TCCTATGTTAATACTT 3-10-3 TCCtatgttaataCTT 415_1 -18.47 46507 416ATCCTATGTTAATACT 4-10-2 ATCCtatgttaataCT 416_1 -18.71 46508 417ATTTCATTAAGTCACCC 3-11-3 ATTtcattaagtcaCCC 417_1 -22.16 47364 418ATTTCATTAAGTCACC 2-10-4 ATttcattaagtCACC 418_1 -18.79 47365 419CTCTCCTCAAGATCAAC 3-11-3 CTCtcctcaagatcAAC 419_1 -20.29 48110 420CTCTCCTCAAGATCAA 3-10-3 CTCtcctcaagatCAA 420_1 -20.33 48111 421CCATACAGTATATACA 4-10-2 CCATacagtatataCA 421_1 -19.53 48186 422CAACTATTATCTTCTT 2-10-4 CAactattatctTCTT 422_1 -16.38 48221 423ACAACTATTATCTTCT 3-10-3 ACAactattatctTCT 423_1 -16.60 48222 424TTGCTTCCAATTTATTT 4-11-2 TTGCttccaatttatTT 424_1 -19.93 50282 425ATCTCATGACCACCTAA 3-11-3 ATCtcatgaccaccTAA 425_1 -21.74 51241 425ATCTCATGACCACCTAA 1-1-1-9-2-1-2 AtCtcatgaccaCCTAA 425_2 -21.11 51241 425ATCTCATGACCACCTAA 1-1-1-8-1-2-3 AtCtcatgaccAccTAA 425_3 -19.96 51241 425ATCTCATGACCACCTAA 1-12-4 AtctcatgaccacCTAA 425_4 -20.40 51241 425ATCTCATGACCACCTAA 3-10-1-1-2 ATCtcatgaccacCTAA 425_5 -20.66 51241 425ATCTCATGACCACCTAA 1-1-1-10-1-1-2 AtCtcatgaccacCTAA 425_6 -18.72 51241425 ATCTCATGACCACCTAA 1-1-1-9-1-1-3 AtCtcatgaccaCcTAA 425_7 -20.59 51241425 ATCTCATGACCACCTAA 1-2-2-7-1-1-3 AtcTCatgaccaCcTAA 425_8 -21.48 51241425 ATCTCATGACCACCTAA 1-3-1-8-4 AtctCatgaccacCTAA 425_9 -21.07 51241 425ATCTCATGACCACCTAA 1-1-3-8-1-1-2 AtCTCatgaccacCtAA 425_10 -21.27 51241426 TCTCATGACCACCTAA 2-10-4 TCtcatgaccacCTAA 426_1 -21.25 51241 427ATCTCATGACCACCTA 3-10-3 ATCtcatgaccacCTA 427_1 -22.56 51242 428TATCTCATGACCACCTA 2-12-3 TAtctcatgaccacCTA 428_1 -21.88 51242 429TTTATCTCATGACCACC 2-11-4 TTtatctcatgacCACC 429_1 -22.37 51244 430TTTATCTCATGACCAC 2-10-4 TTtatctcatgaCCAC 430_1 -19.56 51245 431ATTCTTACCGTCTTTA 4-10-2 ATTCttaccgtcttTA 431_1 -19.52 51358 432TATTCTTACCGTCTTTA 3-11-3 TATtcttaccgtctTTA 432_1 -20.10 51358 433TATTCTTACCGTCTTT 2-10-4 TAttcttaccgtCTTT 433_1 -19.30 51359 434TTATTCTTACCGTCTTT 2-11-4 TTattcttaccgtCTTT 434_1 -19.99 51359 435ATCTGATCTCACACAT 3-10-3 ATCtgatctcacaCAT 435_1 -19.62 51438 436CATCTGATCTCACACAT 4-11-2 CATCtgatctcacacAT 436_1 -20.82 51438 437ACTTCCAGATTTCTACA 2-11-4 ACttccagatttcTACA 437_1 -21.44 51953 438TTTATGTTTACTTCAT 3-10-3 TTTatgtttacttCAT 438_1 -16.05 52150 439TAAAGATCCCATCACTC 3-11-3 TAAagatcccatcaCTC 439_1 -20.31 52549 440TAAAGATCCCATCACT 4-10-2 TAAAgatcccatcaCT 440_1 -18.82 52550 441CCTAAAGATCCCATCAC 2-12-3 CCtaaagatcccatCAC 441_1 -22.32 52551 442ATCATCAGTTACATCA 4-10-2 ATCAtcagttacatCA 442_1 -18.64 52579 443ACTCTCACTGTAACTTT 4-11-2 ACTCtcactgtaactTT 443_1 -19.76 53012 444AACTCTCACTGTAACTT 3-11-3 AACtctcactgtaaCTT 444_1 -18.53 53013 445ACTCTCACTGTAACTT 3-10-3 ACTctcactgtaaCTT 445_1 -19.04 53013 446AACTCTCACTGTAACT 4-10-2 AACTctcactgtaaCT 446_1 -17.97 53014 447CAACTCTCACTGTAACT 4-11-2 CAACtctcactgtaaCT 447_1 -20.01 53014 448CCTTTCATTAACATTTA 3-11-3 CCTttcattaacatTTA 448_1 -19.03 54198 449TTCCTTTCATTAACATTT 4-12-2 TTCCtttcattaacatTT 449_1 -19.92 54199 450TAATCCTATTCCAACT 3-10-3 TAAtcctattccaACT 450_1 -18.05 54232 451CTAATCCTATTCCAAC 2-10-4 CTaatcctattcCAAC 451_1 -18.65 54233 452CTCTAATCCTATTCCA 3-10-3 CTCtaatcctattCCA 452_1 -22.58 54235 453TCTCTAATCCTATTCC 4-10-2 TCTCtaatcctattCC 453_1 -21.78 54236 454TTGTCTCTAATCCTATT 2-11-4 TTgtctctaatccTATT 454_1 -19.70 54238 455TTGTCTCTAATCCTAT 2-10-4 TTgtctctaatcCTAT 455_1 -19.45 54239 456TCTTTAAGCTTCCCAC 2-10-4 TCtttaagcttcCCAC 456_1 -22.96 54609 457AAACTACCCTGCACAA 3-10-3 AAActaccctgcaCAA 457_1 -18.41 54924 458CCATGCTACATAAACC 4-10-2 CCATgctacataaaCC 458_1 -22.25 55337 459TCCATGCTACATAAAC 4-10-2 TCCAtgctacataaAC 459_1 -18.64 55338 460ACTCCTAAGAATTACA 4-10-2 ACTCctaagaattaCA 460_1 -17.62 59565 461GAAACTATTACTCCTA 2-10-4 GAaactattactCCTA 461_1 -19.06 59574 462TGAAACTATTACTCCT 3-10-3 TGAaactattactCCT 462_1 -19.30 59575 463ATGAAACTATTACTCC 2-10-4 ATgaaactattaCTCC 463_1 -17.96 59576 464AACAACTCATGCCACA 2-10-4 AAcaactcatgcCACA 464_1 -19.72 60012 465AAATATTGCCACCATT 2-10-4 AAatattgccacCATT 465_1 -17.78 60298 466GTTACATATTCTTTCAC 3-11-3 GTTacatattctttCAC 466_1 -18.76 60448 467TCATACTTGCTTTAAT 4-10-2 TCATacttgctttaAT 467_1 -17.29 60821 468ATCCTGATAATTAACT 4-10-2 ATCCtgataattaaCT 468_1 -17.73 61925 469CCTTAATCTGTATCAC 3-10-3 CCTtaatctgtatCAC 469_1 -19.92 62287 470ATACACAGCACATATT 2-10-4 ATacacagcacaTATT 470_1 -17.58 62422 471TCAGAATAATTCTCCT 3-10-3 TCAgaataattctCCT 471_1 -19.81 62443 472TCTTCAGCTTTCTAAAT 4-11-2 TCTTcagctttctaaAT 472_1 -18.58 64113 473AGTCCTTCCTTTAACCA 2-13-2 AGtccttcctttaacCA 473_1 -22.20 64461 474TAGTCCTTCCTTTAACC 2-13-2 TAgtccttcctttaaCC 474_1 -22.12 64462 475TTTAACCTTGCTTATA 2-10-4 TTtaaccttgctTATA 475_1 -17.50 65272 476ATCCCTTTGTAATCAT 4-10-2 ATCCctttgtaatcAT 476_1 -20.31 66840 477CTTGCATTTCTAATTAC 3-11-3 CTTgcatttctaatTAC 477_1 -18.09 67426 478CTTGTCAAATCATTTCT 4-11-2 CTTGtcaaatcatttCT 478_1 -19.10 68194 479CCATCTAATGATTATT 4-10-2 CCATctaatgattaTT 479_1 -17.28 68328 480TATCAGTTATCCAATA 4-10-2 TATCagttatccaaTA 480_1 -17.39 68805 481TCACTGCCATCAATAC 4-10-2 TCACtgccatcaatAC 481_1 -19.71 68921 482TGTCATCTACAAATCA 4-10-2 TGTCatctacaaatCA 482_1 -18.01 70133 483CTCTTTAGATTCATCC 4-10-2 CTCTttagattcatCC 483_1 -20.94 72377 484ACTCTTTAGATTCATC 2-10-4 ACtctttagattCATC 484_1 -17.81 72378 485CAACTCTATGACTACC 2-10-4 CAactctatgacTACC 485_1 -20.07 72826 486ACCTGTAATACTTCTT 4-10-2 ACCTgtaatacttcTT 486_1 -19.67 72861 487GAATTCTTTATTCCTCC 2-11-4 GAattctttattcCTCC 487_1 -22.53 72887 488ATCTGAATCAAACCTT 2-10-4 ATctgaatcaaaCCTT 488_1 -17.97 73474 489ACTTTACTGCCATAATC 3-11-3 ACTttactgccataATC 489_1 -19.60 73992 490TTACTCTTAGCAACCT 4-10-2 TTACtcttagcaacCT 490_1 -20.19 74791 491CACCAGTATTTCTTCTT 4-11-2 CACCagtatttcttcTT 491_1 -22.15 74851 492TTCACCAGTATTTCTTC 4-11-2 TTCAccagtatttctTC 492_1 -20.43 74853 493CCAAATAAGCAAACTC 3-10-3 CCAaataagcaaaCTC 493_1 -17.54 75840 494CCCAAATAAGCAAACT 4-10-2 CCCAaataagcaaaCT 494_1 -20.23 75841 495GACTACATTCTCAATA 3-10-3 GACtacattctcaATA 495_1 -17.49 76238 496TTGTCAATCTTTATTCT 4-11-2 TTGTcaatctttattCT 496_1 -18.85 76254 497AGCTTACCAAATATTC 4-10-2 AGCTtaccaaatatTC 497_1 -18.68 76811 498TTACACATGTATATCC 3-10-3 TTAcacatgtataTCC 498_1 -18.23 77114 499ATCCTGTTAATACCAT 2-10-4 ATcctgttaataCCAT 499_1 -20.41 80468 500TTCTTAGTCACACACA 4-10-2 TTCTtagtcacacaCA 500_1 -19.37 81047 501TTCTGTTTCCATTTACA 4-11-2 TTCTgtttccatttaCA 501_1 -21.31 82233 502TCTATATCAAGTTCCTT 2-11-4 TCtatatcaagttCCTT 502_1 -20.95 84166 503ATTCAGTTACCAACTA 3-10-3 ATTcagttaccaaCTA 503_1 -18.37 85392 504GCTTCTACTTAAATAT 3-10-3 GCTtctacttaaaTAT 504_1 -17.58 86974 505CCCTCAAAGTAATTTC 4-10-2 CCCTcaaagtaattTC 505_1 -20.53 87728 506AACATGTAATTTCCAT 2-10-4 AAcatgtaatttCCAT 506_1 -17.21 87810 507CCAGACTCCAATATTT 4-10-2 CCAGactccaatatTT 507_1 -20.78 88417 508CTTAGACTTCACCTTTC 2-11-4 CTtagacttcaccTTTC 508_1 -20.56 88991 509CTGCTTAATTATATCA 4-10-2 CTGCttaattatatCA 509_1 -18.85 90228 510AAATTGTCTACCTTCCT 2-12-3 AAattgtctaccttCCT 510_1 -20.62 90474 511CACTTAGAATATCCCT 2-10-4 CActtagaatatCCCT 511_1 -22.28 91625 512ATCCAAAGTTTCTTTC 4-10-2 ATCCaaagtttcttTC 512_1 -18.64 91885 513ATATTTGTCACCTAAC 4-10-2 ATATttgtcacctaAC 513_1 -17.12 92976 514CTATTCTCAGTATTAT 3-10-3 CTAttctcagtatTAT 514_1 -17.42 94304 515CCATTCAATGATCACT 2-10-4 CCattcaatgatCACT 515_1 -20.55 94528 516CACTAGTACTCTTATT 4-10-2 CACTagtactcttaTT 516_1 -18.01 95653 517GCCACAACATCTATTT 4-10-2 GCCAcaacatctatTT 517_1 -21.53 96751 518AGCACATATACCATCA 4-10-2 AGCAcatataccatCA 518_1 -21.98 97636 519GTCATCTAACTTCTTAC 3-11-3 GTCatctaacttctTAC 519_1 -19.25 98480 520TGTCATCTAACTTCTTA 4-11-2 TGTCatctaacttctTA 520_1 -19.69 98481 521CCCTTATAGTTATTAA 3-10-3 CCCttatagttatTAA 521_1 -19.32 99646 522TCCATAGAATTCTTCA 4-10-2 TCCAtagaattcttCA 522_1 -19.92 100334 523TTGATTCCACCATTAA 3-10-3 TTGattccaccatTAA 523_1 -18.05 101110 524CAGCCATAAACTATAT 4-10-2 CAGCcataaactatAT 524_1 -18.60 101898 525TATGACTTATTCCATA 2-10-4 TAtgacttattcCATA 525_1 -17.88 102558 526GTTAACCTATATTTCA 4-10-2 GTTAacctatatttCA 526_1 -17.69 103589 527TGTCTATTCTCTTCATT 4-11-2 TGTCtattctcttcaTT 527_1 -20.62 104309 528TTACTCTTTGATTTCAT 3-11-3 TTActctttgatttCAT 528_1 -18.39 105686 529GATAATTCCAAATCCC 2-10-4 GAtaattccaaaTCCC 529_1 -20.99 107972 530TCTTATCCTTGAATTTC 4-11-2 TCTTatccttgaattTC 530_1 -18.85 108257 531ATATCCCTTGATTATCC 3-11-3 ATAtcccttgattaTCC 531_1 -22.75 109407 532TTAGTATACCCTTTAT 3-10-3 TTAgtatacccttTAT 532_1 -18.67 110210 533CTCTTTGTCAAATACT 4-10-2 CTCTttgtcaaataCT 533_1 -18.16 110768 534CCAAACTGTCTTCTAAT 2-11-4 CCaaactgtcttcTAAT 534_1 -19.87 111811 535TCCAAACTGTCTTCTAA 3-12-2 TCCaaactgtcttctAA 535_1 -18.33 111812 536CCAGCATATTATATAC 3-10-3 CCAgcatattataTAC 536_1 -18.96 112149 537TCCAGCATATTATATA 4-10-2 TCCAgcatattataTA 537_1 -19.41 112150 538TCATTGAACAACTCTTC 4-11-2 TCATtgaacaactctTC 538_1 -18.01 112945 539CTGCCATCTTTATTTAT 4-11-2 CTGCcatctttatttAT 539_1 -21.89 113533 540TGAAACATTCTTCCCAC 2-12-3 TGaaacattcttccCAC 540_1 -19.76 114274 541TTTATTAGATTACTCC 2-10-4 TTtattagattaCTCC 541_1 -17.38 114495 542TTCCAGCTTATTTACCT 3-12-2 TTCcagcttatttacCT 542_1 -21.28 114831 543AGCATCATATAAACCT 3-10-3 AGCatcatataaaCCT 543_1 -20.62 115355 544GTACTTACACATCTAT 2-10-4 GTacttacacatCTAT 544_1 -18.96 116105 545TGTACTTACACATCTA 3-10-3 TGTacttacacatCTA 545_1 -19.38 116106 546ATTTCTCTATGTCACAT 3-11-3 ATTtctctatgtcaCAT 546_1 -19.28 117096 547CAAACCTACGTCTCTC 2-10-4 CAaacctacgtcTCTC 547_1 -20.87 117189 548GTATTTACTCTTTACCT 3-11-3 GTAtttactctttaCCT 548_1 -22.15 117476 549CTAATGCAATAACCCA 2-10-4 CTaatgcaataaCCCA 549_1 -21.79 118293 550ACTAATGCAATAACCC 3-10-3 ACTaatgcaataaCCC 550_1 -20.53 118294 551AGCTCTAAACCTTCAA 3-10-3 AGCtctaaaccttCAA 551_1 -20.51 118756 552TATTTGTCACCAAACC 3-10-3 TATttgtcaccaaACC 552_1 -19.63 119621 553CTCAGACATCTCAATA 4-10-2 CTCAgacatctcaaTA 553_1 -19.25 120655 554TCTCAGCTTCTTCAAAT 2-12-3 TCtcagcttcttcaAAT 554_1 -18.33 123733 555GCCAATACCCACAAAC 3-10-3 GCCaatacccacaAAC 555_1 -22.03 124163 556CCTCTGACAACCATTA 4-10-2 CCTCtgacaaccatTA 556_1 -22.57 125512 557CAGATAACTCTAAACC 4-10-2 CAGAtaactctaaaCC 557_1 -18.43 126882 558CTAACTGTTTCTCAATT 3-11-3 CTAactgtttctcaATT 558_1 -18.10 127105 559CCAAGATAATCATCAT 3-10-3 CCAagataatcatCAT 559_1 -18.37 127809 560TACATATTGTACTTCT 4-10-2 TACAtattgtacttCT 560_1 -17.48 129020 561TAGCCTACTTTAATAT 4-10-2 TAGCctactttaatAT 561_1 -18.67 129205 562CATTTACAAGCACATA 2-10-4 CAtttacaagcaCATA 562_1 -17.81 129928 563TTATTCTGACACACTT 3-10-3 TTAttctgacacaCTT 563_1 -17.49 130020 564TACATTGACACCTAAT 4-10-2 TACAttgacacctaAT 564_1 -17.37 130884 565TTTACATTGACACCTA 2-10-4 TTtacattgacaCCTA 565_1 -19.42 130886 566TGTATATAACTATTCC 4-10-2 TGTAtataactattCC 566_1 -17.79 131404 567GAATCTTCTAATTCCAC 2-11-4 GAatcttctaattCCAC 567_1 -20.40 132514 568TGCTCACTAACTACAC 3-10-3 TGCtcactaactaCAC 568_1 -20.66 133367 569TGCTACCATCATTACCT 2-13-2 TGctaccatcattacCT 569_1 -21.32 136198 570TTTATCAATATCTTCTCACT 1-13-1-1-1-1-2 TttatcaatatcttCtCaCT 570_1 -19.695784 570 TTTATCAATATCTTCTCACT 1-2-1-10-1-2-3 TttAtcaatatcttCtcACT 570_2-19.67 5784 570 TTTATCAATATCTTCTCACT 1-5-1-7-1-2-3 TttatcAatatcttCtcACT570_3 -19.65 5784 570 TTTATCAATATCTTCTCACT 1-1-1-11-1-3-2TtTatcaatatcttCtcaCT 570_4 -19.75 5784 570 TTTATCAATATCTTCTCACT1-2-1-2-1-11-2 TttAtcAatatcttctcaCT 570_5 -18.21 5784 570TTTATCAATATCTTCTCACT 1-4-1-8-1-3-2 TttatCaatatcttCtcaCT 570_6 -19.695784 570 TTTATCAATATCTTCTCACT 1-2-1-2-1-9-1-1-2 TttAtcAatatcttctCaCT570_7 -18.88 5784 570 TTTATCAATATCTTCTCACT 1-2-1-1-1-11-3TttAtCaatatcttctcACT 570_8 -19.36 5784 570 TTTATCAATATCTTCTCACT1-4-1-10-1-1-2 TttatCaatatcttctCaCT 570_9 -19.38 5784 570TTTATCAATATCTTCTCACT 2-1-1-10-1-1-1-1-2 TTTAtcaatatcttCtCaCT 570_10-20.60 5784 570 TTTATCAATATCTTCTCACT 1-4-1-8-1-1-1-1-2TttatCaatatcttCtCaCT 570_11 -20.36 5784 570 TTTATCAATATCTTCTCACT1-2-1-1-1-8-1-2-3 TttAtCaatatcttCtcACT 570_12 -20.34 5784 570TTTATCAATATCTTCTCACT 1-2-1-2-1-7-1-3-2 TttAtcAatatcttCtcaCT 570_13-19.19 5784 570 TTTATCAATATCTTCTCACT 1-1-2-1-1-10-1-1-2TtTAtCaatatcttctCaCT 570_14 -21.24 5784 571 TTTATCAATATCTTCTCAC1-12-2-1-3 TttatcaatatctTCtCAC 571_1 -19.16 5785 571 TTTATCAATATCTTCTCAC2-1-1-1-1-6-2-2-3 TTrAtCaatatcTTctCAC 571_2 -20.17 5785 571TTTATCAATATCTTCTCAC 3-2-1-7-2-2-2 TTTatCaatatctTCtcAC 571_3 -19.79 5785571 TTTATCAATATCTTCTCAC 1-2-3-8-1-2-2 TttATCaatatcttCtcAC 571_4 -18.785785 571 TTTATCAATATCTTCTCAC 1-4-1-9-4 TttatCaatatcttcTCAC 571_5 -19.065785 571 TTTATCAATATCTTCTCAC 2-1-1-1-1-8-1-1-3 TTrAtCaatatcttCtCAC 571_6-19.75 5785 571 TTTATCAATATCTTCTCAC 1-1-1-2-1-6-1-3-3TtTatCaatatcTtctCAC 571_7 -19.11 5785 571 TTTATCAATATCTTCTCAC2-1-3-6-1-4-2 TTTATCaatatcTtctcAC 571_8 -19.13 5785 571TTTATCAATATCTTCTCAC 4-12-3 TTTAtcaatatcttctCAC 571_9 -20.38 5785 571TTTATCAATATCTTCTCAC 1-1-2-1-1-6-1-3-3 TtTAtCaatatoTtctCAC 571_10 -20.245785 571 TTTATCAATATCTTCTCAC 2-1-1-1-1-7-2-2-2 TTrAtCaatatctTCtcAC571_11 -18.65 5785 571 TTTATCAATATCTTCTCAC 3-2-1-8-1-1-3TTTatCaatatottCtCAC 571_12 -20.89 5785 571 TTTATCAATATCTTCTCAC1-3-2-8-1-1-3 TttaTCaatatottCtCAC 571_13 -19.96 5785 571TTTATCAATATCTTCTCAC 1-2-1-1-1-9-4 TttAtCaatatottcTCAC 571_14 -19.16 5785572 TTTATCAATATCTTCTCA 2-1-1-1-1-7-2-1-2 TTrAtCaatatctTCtCA 572_1 -18.695786 572 TTTATCAATATCTTCTCA 3-2-1-6-1-1-1-1-2 TTTatCaatatoTtCtCA 572_2-19.36 5786 572 TTTATCAATATCTTCTCA 1-4-1-6-1-1-4 TttatCaatatoTtCTCA572_3 -19.19 5786 572 TTTATCAATATCTTCTCA 1-2-3-6-1-2-3TttATCaatatoTtcTCA 572_4 -19.56 5786 572 TTTATCAATATCTTCTCA4-1-1-7-1-2-2 TTTAtCaatatotTctCA 572_5 -19.37 5786 572TTTATCAATATCTTCTCA 1-2-3-8-1-1-2 TttATCaatatottCtCA 572_6 -18.83 5786572 TTTATCAATATCTTCTCA 3-2-1-9-3 TTTatCaatatottcTCA 572_7 -19.07 5786572 TTTATCAATATCTTCTCA 1-2-1-10-4 TttAtcaatatottCTCA 572_8 -18.10 5786572 TTTATCAATATCTTCTCA 4-10-1-1-2 TTTAtcaatatottCtCA 572_9 -19.31 5786572 TTTATCAATATCTTCTCA 2-1-3-6-1-1-1-1-2 TTTATCaatatoTtCtCA 572_10-20.15 5786 572 TTTATCAATATCTTCTCA 3-2-1-6-1-2-3 TTTatCaatatoTtcTCA572_11 -19.59 5786 572 TTTATCAATATCTTCTCA 1-1-2-1-1-7-2-1-2TtTAtCaatatotTCtCA 572_12 -19.64 5786 572 TTTATCAATATCTTCTCA 4-9-1-1-3TTTAtcaatatotTcTCA 572_13 -19.90 5786 572 TTTATCAATATCTTCTCA 1-3-2-8-4TttaTCaatatcttCTCA 572_14 -19.80 5786 573 TATACCTTTCTTTAACCCTT1-4-1-10-1-1-2 TatacCtttctttaacCcTT 573_1 -22.72 8116 573TATACCTTTCTTTAACCCTT 2-4-1-11-2 TAtaccTttctttaacccTT 573_2 -22.80 8116573 TATACCTTTCTTTAACCCTT 1-3-1-10-1-2-2 TataCctttctttaaCccTT 573_3-22.72 8116 573 TATACCTTTCTTTAACCCTT 1-4-1-9-1-2-2 TatacCtttctttaaCccTT573_4 -22.82 8116 573 TATACCTTTCTTTAACCCTT 1-5-1-9-1-1-2TataccTttctttaacCcTT 573_5 -22.35 8116 573 TATACCTTTCTTTAACCCTT1-5-1-1-1-2 TatacctttctttaacCcTT 573_6 -21.83 8116 573TATACCTTTCTTTAACCCTT 1-2-1-1-1-10-1-1-2 TatAcCtttctttaacCcTT 573_7-22.91 8116 573 TATACCTTTCTTTAACCCTT 2-2-1-1-1-11-2 TAtaCcTttctttaacccTT573_8 -23.58 8116 573 TATACCTTTCTTTAACCCTT 2-3-1-12-2TAtacCtttctttaacccTT 573_9 -23.17 8116 573 TATACCTTTCTTTAACCCTT1-3-1-8-2-1-1-1-2 TataCctttctttAAcCcTT 573_10 -23.35 8116 573TATACCTTTCTTTAACCCTT 2-2-1-1-1-7-1-1-1-1-2 TAtaCcTttctttaAcCcTT 573_11-24.68 8116 573 TATACCTTTCTTTAACCCTT 2-4-1-8-2-1-2 TAtaccTttctttaaCCcTT573_12 -25.86 8116 573 TATACCTTTCTTTAACCCTT 2-3-1-9-1-2-2TAtacCtttctttaaCccTT 573_13 -23.96 8116 573 TATACCTTTCTTTAACCCTT2-3-1-10-1-1-2 TAtacCtttctttaacCcTT 573_14 -23.85 8116 574TTATACCTTTCTTTAACCCT 1-1-1-10-1-4-2 TtAtacctttcttTaaccCT 574_1 -22.318117 574 TTATACCTTTCTTTAACCCT 1-13-1-1-1-1-2 TtatacctttctttAaCcCT 574_2-22.38 8117 574 TTATACCTTTCTTTAACCCT 1-1-1-3-1-11-2 TtAtacCtttctttaaccCT574_3 -22.47 8117 574 TTATACCTTTCTTTAACCCT 1-3-1-1-1-7-1-3-2TtatAcCtttctttAaccCT 574_4 -22.68 8117 574 TTATACCTTTCTTTAACCCT1-4-1-8-1-3-2 TtataCctttctttAaccCT 574_5 -22.38 8117 574TTATACCTTTCTTTAACCCT 1-1-1-13-1-1-2 TtAtacctttctttaaCcCT 574_6 -22.368117 574 TTATACCTTTCTTTAACCCT 1-3-1-11-1-1-2 TtatAcctttctttaaCcCT 574_7-22.46 8117 574 TTATACCTTTCTTTAACCCT 1-1-1-2-1-12-2 TtAtaCctttctttaaccCT574_8 -22.36 8117 574 TTATACCTTTCTTTAACCCT 1-5-1-11-2TtatacCtttctttaaccCT 574_9 -22.37 8117 574 TTATACCTTTCTTTAACCCT1-1-1-2-1-10-1-1-2 TtAtaCctttctttaaCcCT 574_10 -23.14 8117 574TTATACCTTTCTTTAACCCT 1-1-1-3-1-9-1-1-2 TtAtacCtttctttaaCcCT 574_11-23.25 8117 574 TTATACCTTTCTTTAACCCT 1-1-1-3-1-10-3 TtAtacCtttctttaacCCT574_12 -24.75 8117 574 TTATACCTTTCTTTAACCCT 1-1-1-2-2-11-2TtAtaCCtttctttaaccCT 574_13 -24.85 8117 574 TTATACCTTTCTTTAACCCT1-3-1-1-1-11-2 TtatAcCtttctttaaccCT 574_14 -22.56 8117 575TTTATACCTTTCTTTAACCC 1-2-1-9-1-4-2 TttAtacctttctTtaacCC 575_1 -21.698118 575 TTTATACCTTTCTTTAACCC 1-12-1-4-2 TttatacctttctTtaacCC 575_2-21.59 8118 575 TTTATACCTTTCTTTAACCC 1-12-1-1-1-2-2 TttatacctttctTtAacCC575_3 -21.71 8118 575 TTTATACCTTTCTTTAACCC 1-4-1-10-1-1-2TttatAcctttctttaAcCC 575_4 -21.90 8118 575 TTTATACCTTTCTTTAACCC1-13-1-3-2 TttatacctttcttTaacCC 575_5 -22.01 8118 575TTTATACCTTTCTTTAACCC 2-1-1-14-2 TTTAtacctttctttaacCC 575_6 -22.20 8118575 TTTATACCTTTCTTTAACCC 1-14-2-1-2 TttatacctttctttAAcCC 575_7 -22.028118 575 TTTATACCTTTCTTTAACCC 1-14-1-2-2 TttatacctttctttAacCC 575_8-21.41 8118 575 TTTATACCTTTCTTTAACCC 1-15-1-1-2 TttatacctttctttaAcCC575_9 -21.71 8118 575 TTTATACCTTTCTTTAACCC 2-1-1-9-1-4-2TTTAtacctttctTtaacCC 575_10 -22.50 8118 575 TTTATACCTTTCTTTAACCC1-2-1-10-1-3-2 TttAtacctttcttTaacCC 575_11 -22.11 8118 575TTTATACCTTTCTTTAACCC 1-4-2-8-2-1-2 TttatACctttctttAAcCC 575_12 -23.408118 575 TTTATACCTTTCTTTAACCC 1-2-1-2-1-9-1-1-2 TttAtaCctttctttaAcCC575_13 -22.59 8118 575 TTTATACCTTTCTTTAACCC 1-1-2-14-2TtTAtacctttctttaacCC 575_14 -23.15 8118 576 TTTTATACCTTTCTTTAACC1-1-1-10-2-3-2 TtTtatacctttcTTtaaCC 576_1 -21.12 8119 576TTTTATACCTTTCTTTAACC 1-3-1-8-1-4-2 TtttAtacctttcTttaaCC 576_2 -20.108119 576 TTTTATACCTTTCTTTAACC 1-1-1-10-1-2-4 TtTtatacctttcTttAACC 576_3-21.45 8119 576 TTTTATACCTTTCTTTAACC 3-11-1-1-1-1-2 TTTtatacctttctTtAaCC576_4 -21.54 8119 576 TTTTATACCTTTCTTTAACC 2-4-1-7-1-3-2TTttatAcctttctTtaaCC 576_5 -20.80 8119 576 TTTTATACCTTTCTTTAACC1-14-1-2-2 TtttatacctttcttTaaCC 576_6 -20.22 8119 576TTTTATACCTTTCTTTAACC 1-15-1-1-2 TtttatacctttctttAaCC 576_7 -19.61 8119576 TTTTATACCTTTCTTTAACC 1-5-1-10-3 TtttatAcctttctttaACC 576_8 -20.518119 576 TTTTATACCTTTCTTTAACC 1-1-2-14-2 TtTTatacctttctttaaCC 576_9-21.03 8119 576 TTTTATACCTTTCTTTAACC 1-1-2-10-1-1-1-1-2TtTTatacctttctTtAaCC 576_10 -21.46 8119 576 TTTTATACCTTTCTTTAACC2-2-1-9-1-3-2 TTttAtacctttctTtaaCC 576_11 -20.70 8119 576TTTTATACCTTTCTTTAACC 1-5-1-7-1-3-2 TtttatAcctttctTtaaCC 576_12 -19.998119 576 TTTTATACCTTTCTTTAACC 1-1-1-12-2-1-2 TtTtatacctttcttTAaCC 576_13-21.68 8119 576 TTTTATACCTTTCTTTAACC 1-1-1-1-1-13-2 TtTtAtacctttctttaaCC576_14 -19.89 8119 577 TTTTTATACCTTTCTTTAAC 1-12-1-2-4TttttatacctttCttTAAC 577_1 -19.19 8120 577 TTTTTATACCTTTCTTTAAC1-2-1-9-1-1-2-1-2 TttTtatacctttCtTTaAC 577_2 -18.96 8120 577TTTTTATACCTTTCTTTAAC 2-12-3-1-2 TTtttatacctttcTTTaAC 577_3 -19.52 8120577 TTTTTATACCTTTCTTTAAC 1-1-1-2-1-7-2-3-2 TtTttAtacctttCTttaAC 577_4-18.71 8120 577 TTTTTATACCTTTCTTTAAC 4-9-1-1-1-2-2 TTTTtatacctttCtTtaAC577_5 -19.85 8120 577 TTTTTATACCTTTCTTTAAC 3-1-1-8-1-1-1-1-3TTTtTatacctttCtTtAAC 577_6 -20.08 8120 577 TTTTTATACCTTTCTTTAAC2-1-2-8-2-2-3 TTtTTatacctttCTttAAC 577_7 -20.97 8120 577TTTTTATACCTTTCTTTAAC 1-1-2-10-2-1-3 TtTTtatacctttcTTTAAC 577_8 -18.898120 577 TTTTTATACCTTTCTTTAAC 1-3-2-7-1-4-2 TtttTAtacctttCtttaAC 577_9-18.97 8120 577 TTTTTATACCTTTCTTTAAC 1-2-1-9-2-1-1-1-2TttTtatacctttCTtTaAC 577_10 -19.34 8120 577 TTTTTATACCTTTCTTTAAC2-3-1-7-2-2-3 TTtttAtacctttCTttAAC 577_11 -19.53 8120 577TTTTTATACCTTTCTTTAAC 1-1-2-9-1-1-1-1-3 TtTTtatacctttCtTtAAC 577_12-18.84 8120 577 TTTTTATACCTTTCTTTAAC 1-3-2-7-1-1-1-2-2TtttTAtacctttCtTtaAC 577_13 -19.27 8120 577 TTTTTATACCTTTCTTTAAC3-1-1-8-1-2-1-1-2 TTTtTatacctttCttTaAC 577_14 -20.20 8120 578TTTTTTCTTACTATCTTCAA 1-5-1-7-2-2-2 TtttttCttactatCTtcAA 578_1 -19.028584 578 TTTTTTCTTACTATCTTCAA 2-2-1-1-1-7-1-1-1-1-2 TTttTtCttactatCtTcAA578_2 -19.31 8584 578 TTTTTTCTTACTATCTTCAA 1-2-2-9-1-2-3TttTTtcttactatCttCAA 578_3 -20.05 8584 578 TTTTTTCTTACTATCTTCAA1-1-1-1-1-1-1-7-1-3-2 TtTtTtCttactatCttcAA 578_4 -18.43 8584 578TTTTTTCTTACTATCTTCAA 3-3-1-8-1-2-2 TTTtttCttactatcTtcAA 578_5 -18.998584 578 TTTTTTCTTACTATCTTCAA 2-1-2-1-1-8-1-2-2 TTtTTtCttactatcttcAA578_6 -19.29 8584 578 TTTTTTCTTACTATCTTCAA 1-1-3-1-1-9-1-1-2TtTTTtCttactatctTcAA 578_7 -19.15 8584 578 TTTTTTCTTACTATCTTCAA2-1-1-11-1-1-3 TTtTttcttactatcTtCAA 578_8 -19.58 8584 578TTTTTTCTTACTATCTTCAA 1-4-1-10-4 TttttTcttactatctTCAA 578_9 -19.31 8584579 TTTTTTTCTTACTATCTTCA 1-12-1-1-1-2-2 TttttttcttactAtCttCA 579_1-19.29 8585 579 TTTTTTTCTTACTATCTTCA 2-1-1-9-1-4-2 TTtTtttcttactAtcttCA579_2 -19.42 8585 579 TTTTTTTCTTACTATCTTCA 1-1-1-2-1-7-1-4-2TtTttTtcttactAtcttCA 579_3 -18.91 8585 579 TTTTTTTCTTACTATCTTCA1-1-2-9-1-2-1-1-2 TtTTtttcttactAtcTtCA 579_4 -19.94 8585 579TTTTTTTCTTACTATCTTCA 1-3-2-10-1-1-2 TttttTtcttactatcTtCA 579_5 -19.848585 579 TTTTTTTCTTACTATCTTCA 2-3-1-12-2 TTtttTtcttactatcttCA 579_6-19.33 8585 579 TTTTTTTCTTACTATCTTCA 3-15-2 TTTttttcttactatcttCA 579_7-19.84 8585 579 TTTTTTTCTTACTATCTTCA 1-2-2-13-2 TttTTttcttactatcttCA579_8 -19.33 8585 579 TTTTTTTCTTACTATCTTCA 1-14-1-2-2TttttttcttactatCttCA 579_9 -19.19 8585 580 ATTTTTTTCTTACTATCTTC1-4-1-8-1-1-1-1-2 AttttTttcttactAtCtTC 580_1 -18.09 8586 580ATTTTTTTCTTACTATCTTC 2-1-1-10-1-2-3 ATtTttttcttactAtcTTC 580_2 -19.398586 580 ATTTTTTTCTTACTATCTTC 1-3-2-8-1-2-3 AtttTTttcttactAtcTTC 580_3-18.95 8586 580 ATTTTTTTCTTACTATCTTC 1-5-1-6-1-3-3 AtttttTtcttacTatcTTC580_4 -18.98 8586 580 ATTTTTTTCTTACTATCTTC 2-2-1-1-1-7-1-3-2ATttTtTtcttactAtctTC 580_5 -18.66 8586 580 ATTTTTTTCTTACTATCTTC1-1-3-8-1-4-2 AtTTTtttcttacTatctTC 580_6 -19.58 8586 580ATTTTTTTCTTACTATCTTC 2-1-1-12-1-1-2 ATtTttttcttactatCtTC 580_7 -19.248586 580 ATTTTTTTCTTACTATCTTC 1-1-1-2-1-11-3 AtTttTttcttactatcTTC 580_8-18.34 8586 580 ATTTTTTTCTTACTATCTTC 1-1-2-1-2-11-2 AtTTtTTtcttactatctTC580_9 -18.94 8586 581 AATTTTTTTCTTACTATCTT 1-4-1-7-1-1-1-1-3AatttTtttcttaCtAtCTT 581_1 -18.53 8587 581 AATTTTTTTCTTACTATCTT1-3-1-1-1-6-2-3-2 AattTtTttcttaCTatcTT 581_2 -18.69 8587 581AATTTTTTTCTTACTATCTT 1-1-2-10-2-2-2 AaTTtttttcttacTAtcTT 581_3 -18.808587 581 AATTTTTTTCTTACTATCTT 2-1-1-1-1-8-1-2-3 AAtTtTtttcttacTatCTT581_4 -19.20 8587 581 AATTTTTTTCTTACTATCTT 4-2-1-7-1-3-2AATTtttttcttacTatcTT 581_5 -19.30 8587 581 AATTTTTTTCTTACTATCTT2-2-2-7-1-1-2-1-2 AAtttTtttcttaCtATcTT 581_6 -19.52 8587 581AATTTTTTTCTTACTATCTT 1-12-1-2-4 AatttttttcttaCtaTCTT 581_7 -19.25 8587581 AATTTTTTTCTTACTATCTT 1-1-4-7-1-4-2 AaTTTTtttcttaCtatcTT 581_8 -19.358587 581 AATTTTTTTCTTACTATCTT 2-1-3-9-1-1-3 AAtTTTtttcttactAtCTT 581_9-19.68 8587 582 GTTTATACCCTTTCCAAT 1-1-1-1-1-7-2-2-2 GtTtAtacccttTCcaAT582_1 -21.48 9209 582 GTTTATACCCTTTCCAAT 1-12-2-1-2 GtttataccctttCCaAT582_2 -22.28 9209 582 GTTTATACCCTTTCCAAT 1-3-1-8-1-1-3GtttAtaccctttCcAAT 582_3 -20.46 9209 582 GTTTATACCCTTTCCAAT1-1-1-1-1-9-1-1-2 GtTtAtaccctttcCaAT 582_4 -20.30 9209 582GTTTATACCCTTTCCAAT 2-11-1-2-2 GTttataccctttCcaAT 582_5 -21.64 9209 582GTTTATACCCTTTCCAAT 1-1-2-9-1-1-3 GtTTataccctttCcAAT 582_6 -21.90 9209582 GTTTATACCCTTTCCAAT 1-1-1-13-2 GtTtataccctttccaAT 582_7 -19.63 9209582 GTTTATACCCTTTCCAAT 1-2-1-12-2 GttTataccctttccaAT 582_8 -20.05 9209582 GTTTATACCCTTTCCAAT 1-13-4 GtttataccctttcCAAT 582_9 -21.59 9209 583TGTTTATACCCTTTCCAA 2-1-1-10-1-1-2 TGtTtataccctttCcAA 583_1 -21.08 9210583 TGTTTATACCCTTTCCAA 1-4-1-6-1-1-1-1-2 TgtttAtaccctTtCcAA 583_2 -19.979210 583 TGTTTATACCCTTTCCAA 1-3-1-9-1-1-2 TgttTataccctttCcAA 583_3-20.30 9210 583 TGTTTATACCCTTTCCAA 2-1-1-1-1-6-1-3-2 TGtTtAtaccctTtccAA583_4 -20.71 9210 583 TGTTTATACCCTTTCCAA 1-2-1-8-1-2-3TgtTtataccctTtcCAA 583_5 -21.40 9210 583 TGTTTATACCCTTTCCAA 1-4-1-9-3TgtttAtaccctttcCAA 583_6 -20.89 9210 583 TGTTTATACCCTTTCCAA 1-1-2-12-2TgTTtataccctttccAA 583_7 -20.27 9210 583 TGTTTATACCCTTTCCAA 1-12-2-1-2TgtttatacccttTCcAA 583_8 -20.56 9210 583 TGTTTATACCCTTTCCAA 2-2-1-11-2TGttTataccctttccAA 583_9 -20.74 9210 584 CTGTTTATACCCTTTCCA1-1-1-10-1-2-2 CtGtttataccctTtcCA 584_1 -22.45 9211 584CTGTTTATACCCTTTCCA 1-12-1-2-2 CtgtttataccctTtcCA 584_2 -22.14 9211 584CTGTTTATACCCTTTCCA 1-1-1-1-1-11-2 CtGtTtataccctttcCA 584_3 -22.45 9211584 CTGTTTATACCCTTTCCA 1-1-1-13-2 CtGtttataccctttcCA 584_4 -22.15 9211584 CTGTTTATACCCTTTCCA 1-2-1-12-2 CtgTttataccctttcCA 584_5 -22.50 9211584 CTGTTTATACCCTTTCCA 1-3-1-11-2 CtgtTtataccctttcCA 584_6 -22.14 9211584 CTGTTTATACCCTTTCCA 1-4-1-10-2 CtgttTataccctttcCA 584_7 -22.57 9211584 CTGTTTATACCCTTTCCA 1-15-2 CtgtttataccctttcCA 584_8 -21.84 9211 585AATTATTTATACACCATCAT 2-1-1-1-1-8-3-1-2 AAtTaTttatacacCATcAT 585_1 -20.7611511 585 AATTATTTATACACCATCAT 3-2-2-6-1-1-2-1-2 AATtaTTtatacaCcATcAT585_2 -20.88 11511 585 AATTATTTATACACCATCAT 1-4-1-7-2-1-1-1-2AattaTttatacaCCaTcAT 585_3 -19.62 11511 585 AATTATTTATACACCATCAT1-3-1-1-1-6-1-3-3 AattAtTtatacaCcatCAT 585_4 -18.98 11511 585AATTATTTATACACCATCAT 1-2-3-7-1-1-1-2-2 AatTATttatacaCcAtcAT 585_5 -19.6511511 585 AATTATTTATACACCATCAT 1-1-2-11-1-1-3 AaTTatttatacaccAtCAT 585_6-19.53 11511 585 AATTATTTATACACCATCAT 2-2-1-9-1-1-4 AAttAtttatacacCaTCAT585_7 -20.11 11511 585 AATTATTTATACACCATCAT 3-1-2-8-1-2-3AATTATttatacacCatCAT 585_8 -21.48 11511 585 AATTATTTATACACCATCAT4-2-1-7-1-3-2 AATTatTtatacacCatcAT 585_9 -19.60 11511 585AATTATTTATACACCATCAT 2-1-1-2-1-6-3-2-2 AAtTatTtatacaCCAtcAT 585_10-21.69 11511 585 AATTATTTATACACCATCAT 1-3-2-7-1-1-1-1-3AattATttatacaCcAtCAT 585_11 -19.97 11511 585 AATTATTTATACACCATCAT2-1-3-8-1-1-1-1-2 AAtTATttatacacCaTcAT 585_12 -20.42 11511 585AATTATTTATACACCATCAT 1-1-2-1-1-8-1-2-3 AaTTaTttatacacCatCAT 585_13-20.49 11511 585 AATTATTTATACACCATCAT 2-1-1-2-1-9-4 AAtTatTtatacaccaTCAT585_14 -20.47 11511 586 AAATTATTTATACACCATCA 1-12-3-1-3AaattatttatacACCaTCA 586_1 -20.58 11512 586 AAATTATTTATACACCATCA1-1-1-2-1-7-1-1-2-1-2 AaAttAtttatacAcCAtCA 586_2 -18.56 11512 586AAATTATTTATACACCATCA 3-2-2-6-2-3-2 AAAttATttatacACcatCA 586_3 -19.6811512 586 AAATTATTTATACACCATCA 4-10-1-2-3 AAATtatttatacaCcaTCA 586_4-20.15 11512 586 AAATTATTTATACACCATCA 1-1-4-8-1-1-1-1-2AaATTAtttatacaCcAtCA 586_5 -20.72 11512 586 AAATTATTTATACACCATCA2-1-2-1-1-7-1-3-2 AAaTTaTttatacaCcatCA 586_6 -19.39 11512 586AAATTATTTATACACCATCA 1-3-2-7-1-1-1-1-3 AaatTAtttatacAcCaTCA 586_7 -19.6511512 586 AAATTATTTATACACCATCA 1-1-3-8-1-2-4 AaATTatttatacAccATCA 586_8-20.88 11512 586 AAATTATTTATACACCATCA 2-2-1-1-1-9-4 AAatTaTttatacaccATCA586_9 -19.63 11512 586 AAATTATTTATACACCATCA 1-1-1-1-1-1-1-6-3-2-2AaAtTaTttatacACCatCA 586_10 -20.95 11512 586 AAATTATTTATACACCATCA1-3-2-7-1-1-2-1-2 AaatTAtttatacAcCAtCA 586_11 -20.00 11512 586AAATTATTTATACACCATCA 2-1-2-1-1-7-1-1-1-1-2 AAaTTaTttatacaCcAtCA 586_12-19.44 11512 586 AAATTATTTATACACCATCA 3-2-1-8-1-2-3 AAAttAtttatacaCcaTCA586_13 -19.00 11512 586 AAATTATTTATACACCATCA 1-1-4-9-1-1-3AaATTAtttatacacCaTCA 586_14 -21.59 11512 587 AAAATTATTTATACACCATC2-3-1-7-1-1-5 AAaatTatttataCaCCATC 587_1 -21.17 11513 587AAAATTATTTATACACCATC 1-2-2-9-6 AaaATtatttatacACCATC 587_2 -21.34 11513587 AAAATTATTTATACACCATC 2-3-2-6-3-1-3 AAaatTAtttataCACcATC 587_3 -20.6711513 587 AAAATTATTTATACACCATC 3-1-1-1-1-7-3-1-2 AAAaTtAtttatacACCaTC587_4 -19.11 11513 587 AAAATTATTTATACACCATC 7-6-1-1-1-2-2AAAATTAtttataCaCcaTC 587_5 -20.66 11513 587 AAAATTATTTATACACCATC1-1-1-1-2-8-2-1-3 AaAaTTatttatacACcATC 587_6 -18.20 11513 587AAAATTATTTATACACCATC 1-1-5-6-2-3-2 AaAATTAtttataCAccaTC 587_7 -20.7111513 587 AAAATTATTTATACACCATC 2-1-3-7-1-2-4 AAaATTatttataCacCATC 587_8-20.87 11513 587 AAAATTATTTATACACCATC 4-1-1-8-1-1-4 AAAAtTatttatacAcCATC587_9 -19.30 11513 587 AAAATTATTTATACACCATC 1-1-2-1-2-6-3-2-2AaAAtTAtttataCACcaTC 587_10 -20.13 11513 587 AAAATTATTTATACACCATC1-2-3-7-1-1-2-1-2 AaaATTatttataCaCCaTC 587_11 -20.44 11513 587AAAATTATTTATACACCATC 3-1-2-7-1-2-4 AAAaTTatttataCacCATC 587_12 -20.2711513 587 AAAATTATTTATACACCATC 3-2-1-8-3-1-2 AAAatTatttatacACCaTC 587_13-19.30 11513 587 AAAATTATTTATACACCATC 2-1-3-8-2-1-3 AAaATTatttatacACcATC587_14 -19.52 11513 588 TAAAATTATTTATACACCAT 2-3-1-7-1-1-5TAaaaTtatttatAcACCAT 588_1 -20.14 11514 588 TAAAATTATTTATACACCAT1-2-1-2-1-6-2-1-4 TaaAatTatttatACaCCAT 588_2 -20.15 11514 588TAAAATTATTTATACACCAT 1-1-1-1-2-8-1-1-4 TaAaATtatttataCaCCAT 588_3 -20.4011514 588 TAAAATTATTTATACACCAT 4-1-2-6-4-1-2 TAAAaTTatttatACACcAT 588_4-21.36 11514 588 TAAAATTATTTATACACCAT 1-3-3-6-3-1-3 TaaaATTatttatACAcCAT588_5 -21.07 11514 588 TAAAATTATTTATACACCAT 2-1-4-7-3-1-2TAaAATTatttataCACcAT 588_6 -21.36 11514 588 TAAAATTATTTATACACCAT3-1-1-1-1-7-2-1-3 TAAaAtTatttataCAcCAT 588_7 -20.41 11514 588TAAAATTATTTATACACCAT 7-6-1-3-3 TAAAATTatttatAcacCAT 588_8 -20.85 11514588 TAAAATTATTTATACACCAT 2-1-2-11-4 TAaAAttatttatacaCCAT 588_9 -19.8211514 588 TAAAATTATTTATACACCAT 2-2-3-6-4-1-2 TAaaATTatttatACACcAT 588_10-21.41 11514 588 TAAAATTATTTATACACCAT 1-1-1-1-3-6-1-2-4TaAaATTatttatAcaCCAT 588_11 -21.15 11514 588 TAAAATTATTTATACACCAT2-1-2-1-1-7-2-1-3 TAaAAtTatttataCAcCAT 588_12 -20.41 11514 588TAAAATTATTTATACACCAT 3-2-2-7-1-1-4 TAAaaTTatttataCaCCAT 588_13 -21.8611514 588 TAAAATTATTTATACACCAT 1-1-2-1-1-9-5 TaAAaTtatttatacACCAT 588_14-19.68 11514 589 TAAAATTATTTATACACCA 1-1-2-1-1-7-6 TaAAaTtatttatACACCA589_1 -20.31 11515 589 TAAAATTATTTATACACCA 1-2-3-6-1-1-5TaaAATtatttaTaCACCA 589_2 -21.36 11515 589 TAAAATTATTTATACACCA 2-3-1-7-6TAaaaTtatttatACACCA 589_3 -20.58 11515 589 TAAAATTATTTATACACCA3-1-2-6-4-1-2 TAAaATtatttaTACAcCA 589_4 -21.36 11515 589TAAAATTATTTATACACCA 4-1-1-6-2-2-3 TAAAaTtatttaTAcaCCA 589_5 -20.51 11515589 TAAAATTATTTATACACCA 2-1-2-7-1-1-1-1-3 TAaAAttatttaTaCaCCA 589_6-19.30 11515 589 TAAAATTATTTATACACCA 1-3-2-6-2-2-3 TaaaATtatttaTAcaCCA589_7 -19.40 11515 589 TAAAATTATTTATACACCA 5-8-2-1-3 TAAAAttatttatACaCCA589_8 -19.77 11515 589 TAAAATTATTTATACACCA 3-1-2-9-4 TAAaATtatttatacACCA589_9 -19.55 11515 589 TAAAATTATTTATACACCA 2-1-3-6-4-1-2TAaAATtatttaTACAcCA 589_10 -21.36 11515 589 TAAAATTATTTATACACCA3-1-2-6-3-1-3 TAAaATtatttaTACaCCA 589_11 -22.18 11515 589TAAAATTATTTATACACCA 1-1-3-7-2-1-4 TaAAAttatttaTAcACCA 589_12 -19.7811515 589 TAAAATTATTTATACACCA 2-2-1-7-1-1-1-1-3 TAaaAttatttaTaCaCCA589_13 -18.76 11515 589 TAAAATTATTTATACACCA 4-1-1-8-5TAAAaTtatttataCACCA 589_14 -21.06 11515 590 ATATTGATTCAATTCCC 2-9-2-1-3ATattgattcaATtCCC 590_1 -21.84 13226 590 ATATTGATTCAATTCCC 1-2-1-7-6AtaTtgattcaATTCCC 590_2 -22.10 13226 590 ATATTGATTCAATTCCC 2-9-1-1-1-1-2ATattgattcaAtTcCC 590_3 -18.59 13226 590 ATATTGATTCAATTCCC 1-1-2-8-5AtATtgattcaaTTCCC 590_4 -21.87 13226 590 ATATTGATTCAATTCCC 1-2-2-7-2-1-2AtaTTgattcaaTTcCC 590_5 -19.29 13226 590 ATATTGATTCAATTCCC 1-3-1-6-2-2-2AtatTgattcaATtcCC 590_6 -18.59 13226 590 ATATTGATTCAATTCCC 1-2-2-6-1-2-3AtaTTgattcaAttCCC 590_7 -20.66 13226 590 ATATTGATTCAATTCCC1-1-1-1-1-7-1-1-3 AtAtTgattcaaTtCCC 590_8 -19.92 13226 590ATATTGATTCAATTCCC 1-1-1-8-1-2-3 AtAttgattcaAttCCC 590_9 -19.01 13226 590ATATTGATTCAATTCCC 4-7-1-3-2 ATATtgattcaAttcCC 590_10 -20.60 13226 590ATATTGATTCAATTCCC 3-1-1-7-1-2-2 ATAtTgattcaaTtcCC 590_11 -20.26 13226590 ATATTGATTCAATTCCC 1-3-1-8-4 AtatTgattcaatTCCC 590_12 -20.37 13226590 ATATTGATTCAATTCCC 2-1-1-10-3 ATaTtgattcaattCCC 590_13 -20.71 13226590 ATATTGATTCAATTCCC 2-2-1-9-3 ATatTgattcaattCCC 590_14 -21.06 13226590 ATATTGATTCAATTCCC 1-1-3-10-2 AtATTgattcaattcCC 590_15 -18.87 13226590 ATATTGATTCAATTCCC 2-2-1-6-2-2-2 ATatTgattcaATtcCC 590_16 -20.2613226 590 ATATTGATTCAATTCCC 3-8-1-1-4 ATAttgattcaAtTCCC 590_17 -22.7113226 590 ATATTGATTCAATTCCC 1-1-3-6-1-2-3 AtATTgattcaAttCCC 590_18-21.57 13226 590 ATATTGATTCAATTCCC 1-1-1-1-1-7-5 AtAtTgattcaaTTCCC590_19 -21.42 13226 590 ATATTGATTCAATTCCC 2-1-1-8-1-1-3ATaTtgattcaaTtCCC 590_20 -21.15 13226 591 GCACATTCTTTCTATACCT1-1-1-1-1-12-2 GcAcAttctttctatacCT 591_1 -21.27 15113 591GCACATTCTTTCTATACCT 1-3-1-12-2 GcacAttctttctatacCT 591_2 -21.12 15113592 GCACATTCTTTCTATACC 1-12-1-2-2 GcacattctttctAtaCC 592_1 -20.07 15114592 GCACATTCTTTCTATACC 1-1-1-1-1-11-2 GcAcAttctttctataCC 592_2 -20.1715114 592 GCACATTCTTTCTATACC 1-3-1-11-2 GcacAttctttctataCC 592_3 -20.0215114 592 GCACATTCTTTCTATACC 1-1-2-11-3 GcACattctttctatACC 592_4 -21.8015114 592 GCACATTCTTTCTATACC 1-1-1-1-2-7-1-1-3 GcAcATtctttctAtACC 592_5-22.11 15114 592 GCACATTCTTTCTATACC 1-1-1-1-2-7-1-2-2 GcAcATtctttctAtaCC592_6 -21.51 15114 592 GCACATTCTTTCTATACC 1-15-2 GcacattctttctataCC592_7 -19.97 15114 592 GCACATTCTTTCTATACC 1-4-1-9-3 GcacaTtctttctatACC592_8 -21.01 15114 592 GCACATTCTTTCTATACC 1-4-1-10-2 GcacaTtctttctataCC592_9 -20.41 15114 592 GCACATTCTTTCTATACC 2-11-1-2-2 GCacattctttctAtaCC592_10 -22.39 15114 592 GCACATTCTTTCTATACC 1-1-1-1-1-8-1-2-2GcAcAttctttctAtaCC 592_11 -20.27 15114 592 GCACATTCTTTCTATACC1-3-1-9-1-1-2 GcacAttctttctaTaCC 592_12 -20.89 15114 592GCACATTCTTTCTATACC 1-1-1-1-1-10-3 GcAcAttctttctatACC 592_13 -20.77 15114592 GCACATTCTTTCTATACC 1-1-1-2-1-10-2 GcAcaTtctttctataCC 592_14 -20.5615114 593 TTATTTCCATTTATTTTCA 1-1-1-1-1-8-3-1-2 TtAtTtccatttaTTTtCA593_1 -19.10 15563 593 TTATTTCCATTTATTTTCA 1-2-2-7-1-1-1-1-3TtaTTtccatttAtTtTCA 593_2 -19.27 15563 593 TTATTTCCATTTATTTTCA2-2-1-8-1-1-1-1-2 TTatTtccatttaTtTtCA 593_3 -18.92 15563 593TTATTTCCATTTATTTTCA 1-1-2-9-1-2-3 TtATttccatttaTttTCA 593_4 -19.41 15563594 TTTATTTCCATTTATTTTCA 1-1-1-11-1-2-3 TtTatttccatttaTttTCA 594_1-19.80 15563 594 TTTATTTCCATTTATTTTCA 1-4-1-7-1-1-1-2-2TttatTtccatttAtTttCA 594_2 -18.34 15563 594 TTTATTTCCATTTATTTTCA1-3-2-9-2-1-2 TttaTTtccatttatTTtCA 594_3 -20.01 15563 594TTTATTTCCATTTATTTTCA 2-1-1-1-1-8-1-1-1-1-2 TTTAtTtccatttaTtTtCA 594_4-19.60 15563 595 ATTTATTTCCATTTATTTTC 1-1-1-2-1-8-3-1-2AtTtaTttccatttATTtTC 595_1 -19.05 15564 595 ATTTATTTCCATTTATTTTC1-3-2-7-1-3-3 AtttATttccattTattTTC 595_2 -19.03 15564 595ATTTATTTCCATTTATTTTC 1-1-2-10-1-2-3 AtTTatttccatttAttTTC 595_3 -18.6015564 595 ATTTATTTCCATTTATTTTC 2-1-1-1-1-8-1-1-1-1-2ATtTaTttccatttAtTtTC 595_4 -18.96 15564 596 TTTATTTCCATTTATTTTC1-1-1-1-1-8-2-1-3 TtTaTttccatttATtTTC 596_1 -18.66 15564 596TTTATTTCCATTTATTTTC 3-2-1-7-3-1-2 TTTatTtccatttATTtTC 596_2 -19.84 15564596 TTTATTTCCATTTATTTTC 2-2-2-7-1-1-4 TTtaTTtccatttAtTTTC 596_3 -19.1215564 596 TTTATTTCCATTTATTTTC 5-7-1-3-3 TTTATttccattTattTTC 596_4 -21.3015564 597 CCATTTATTTCCATTTATTT 1-1-1-11-2-2-2 CcAtttatttccatTTatTT 597_1-19.89 15566 597 CCATTTATTTCCATTTATTT 1-3-1-9-1-1-1-1-2CcatTtatttccatTtAtTT 597_2 -19.00 15566 597 CCATTTATTTCCATTTATTT1-1-1-2-1-8-1-2-3 CcAttTatttccatTtaTTT 597_3 -20.33 15566 597CCATTTATTTCCATTTATTT 1-2-2-1-1-11-2 CcaTTTAtttccatttatTT 597_4 -19.6415566 598 TCCATTTATTTCCATTTATT 2-11-2-3-2 TCcatttatttccATttaTT 598_1-21.22 15567 598 TCCATTTATTTCCATTTATT 2-2-1-8-1-1-1-2-2TCcaTttatttccAtTtaTT 598_2 -20.71 15567 598 TCCATTTATTTCCATTTATT1-1-2-9-1-4-2 TcCAtttatttccAtttaTT 598_3 -20.63 15567 598TCCATTTATTTCCATTTATT 2-1-1-1-1-11-3 TCcAtTtatttccatttATT 598_4 -21.1815567 599 TCCATTTATTTCCATTTAT 2-11-2-2-2 TCcatttatttccATttAT 599_1-20.30 15568 599 TCCATTTATTTCCATTTAT 2-2-1-8-1-1-1-1-2TCcaTttatttccAtTTAT 599_2 -19.80 15568 599 TCCATTTATTTCCATTTAT1-1-2-9-1-3-2 TcCAtttatttccAtttAT 599_3 -19.72 15568 599TCCATTTATTTCCATTTAT 1-1-1-1-2-7-1-3-2 TcCaTTtatttccAtttAT 599_4 -19.5015568 600 TTCCATTTATTTCCATTTAT 1-1-1-2-1-8-1-1-1-1-2TtCcaTttatttccAtTtAT 600_1 -20.12 15568 600 TTCCATTTATTTCCATTTAT1-3-1-10-2-1-2 TtccAtttatttccaTTTAT 600_2 -19.86 15568 600TTCCATTTATTTCCATTTAT 1-1-1-3-1-7-1-3-2 TtCcatTtatttccAtttAT 600_3 -19.6815568 600 TTCCATTTATTTCCATTTAT 1-1-1-1-2-8-1-3-2 TtCcATttatttccAtttAT600_4 -20.68 15568 601 TTTCCATTTATTTCCATTTA 1-4-1-7-1-2-1-1-2TttccAtttatttCcaTtTA 601_1 -20.53 15569 601 TTTCCATTTATTTCCATTTA2-2-1-12-3 TTtcCatttatttccatTTA 601_2 -21.47 15569 601TTTCCATTTATTTCCATTTA 1-2-1-2-1-8-1-2-2 TttCcaTttatttccAttTA 601_3 -20.5315569 601 TTTCCATTTATTTCCATTTA 1-4-1-9-1-2-2 TttccAtttatttccAttTA 601_4-19.37 15569 602 CTTTCCATTTATTTCCATT 1-11-1-1-1-1-3 CtttccatttatTtCcATT602_1 -21.20 15571 602 CTTTCCATTTATTTCCATT 2-2-1-9-1-2-2CTttCcatttatttCcaTT 602_2 -22.00 15571 602 CTTTCCATTTATTTCCATT1-4-1-9-1-1-2 CtttcCatttatttcCaTT 602_3 -20.42 15571 602CTTTCCATTTATTTCCATT 1-3-1-11-3 CtttCcatttatttccATT 602_4 -20.89 15571603 ATCTTTCCATTTATTTCCAT 1-2-1-12-1-1-2 AtcTttccatttatttCcAT 603_1-21.24 15572 603 ATCTTTCCATTTATTTCCAT 1-3-1-1-1-7-1-3-2AtctTtCcatttatTtccAT 603_2 -21.33 15572 603 ATCTTTCCATTTATTTCCAT1-5-1-6-1-4-2 AtctttCcatttaTttccAT 603_3 -21.16 15572 603ATCTTTCCATTTATTTCCAT 1-16-3 AtctttccatttatttcCAT 603_4 -21.95 15572 604TCTTTCCATTTATTTCCAT 2-13-1-1-2 TCtttccatttatttCcAT 604_1 -21.57 15572604 TCTTTCCATTTATTTCCAT 1-2-1-1-1-7-1-1-1-1-2 TctTtCcatttatTtCcAT 604_2-21.35 15572 604 TCTTTCCATTTATTTCCAT 2-14-3 TCtttccatttatttcCAT 604_3-22.80 15572 604 TCTTTCCATTTATTTCCAT 2-3-1-11-2 TCtttCcatttatttccAT604_4 -21.57 15572 605 ATCTTTCCATTTATTTCCA 1-2-1-10-1-2-2AtcTttccatttatTtcCA 605_1 -20.70 15573 605 ATCTTTCCATTTATTTCCA1-3-1-8-1-3-2 AtctTtccatttaTttcCA 605_2 -20.63 15573 605ATCTTTCCATTTATTTCCA 1-1-1-14-2 AtCtttccatttatttcCA 605_3 -20.86 15573605 ATCTTTCCATTTATTTCCA 1-4-1-9-1-1-2 AtcttTccatttattTcCA 605_4 -20.6315573 606 TATCTTTCCATTTATTTCCA 1-4-1-8-2-2-2 TatctTtccatttaTTtcCA 606_1-22.54 15573 606 TATCTTTCCATTTATTTCCA 2-16-2 TAtctttccatttatttcCA 606_2-22.12 15573 606 TATCTTTCCATTTATTTCCA 1-2-1-14-2 TatCtttccatttatttcCA606_3 -21.97 15573 606 TATCTTTCCATTTATTTCCA 1-17-2 TatctttccatttatttcCA606_4 -20.99 15573 607 TATCTTTCCATTTATTTCC 2-12-1-2-2TAtctttccatttaTttCC 607_1 -21.63 15574 607 TATCTTTCCATTTATTTCC1-2-1-13-2 TatCtttccatttatttCC 607_2 -21.04 15574 607TATCTTTCCATTTATTTCC 1-2-2-12-2 TatCTttccatttatttCC 607_3 -22.23 15574607 TATCTTTCCATTTATTTCC 1-4-1-9-1-1-2 TatctTtccatttatTtCC 607_4 -20.6615574 608 AAATCTCAACTACCATTTTT 1-1-1-3-1-7-3-1-2 AaAtctCaactaccATTtTT608_1 -19.53 25248 608 AAATCTCAACTACCATTTTT 3-1-1-9-2-1-3AAAtCtcaactaccATtTTT 608_2 -20.58 25248 608 AAATCTCAACTACCATTTTT1-3-1-8-1-1-5 AaatCtcaactacCaTTTTT 608_3 -20.56 25248 608AAATCTCAACTACCATTTTT 1-1-1-2-1-7-2-2-3 AaAtcTcaactacCAttTTT 608_4 -20.2025248 608 AAATCTCAACTACCATTTTT 1-3-1-1-1-6-1-1-1-2-2AaatCtCaactacCaTttTT 608_5 -19.10 25248 608 AAATCTCAACTACCATTTTT2-3-2-6-1-2-4 AAatcTCaactacCatTTTT 608_6 -21.04 25248 608AAATCTCAACTACCATTTTT 2-1-2-1-1-7-1-3-2 AAaTCtCaactaccAtttTT 608_7 -19.7925248 608 AAATCTCAACTACCATTTTT 1-1-3-11-1-1-2 AaATCtcaactaccatTtTT 608_8-19.97 25248 608 AAATCTCAACTACCATTTTT 3-1-1-1-1-10-3AAAtCtCaactaccattTTT 608_9 -19.95 25248 609 AAAATCTCAACTACCATTTT1-12-4-1-2 AaaatctcaactaCCATtTT 609_1 -21.31 25249 609AAAATCTCAACTACCATTTT 3-11-2-1-3 AAAatctcaactacCAtTTT 609_2 -19.57 25249609 AAAATCTCAACTACCATTTT 2-1-1-1-1-8-2-1-3 AAaAtCtcaactacCAtTTT 609_3-20.33 25249 609 AAAATCTCAACTACCATTTT 1-1-4-9-1-2-2 AaAATCtcaactaccAttTT609_4 -19.46 25249 609 AAAATCTCAACTACCATTTT 1-1-2-2-1-7-2-2-2AaAAtcTcaactacCAttTT 609_5 -19.13 25249 609 AAAATCTCAACTACCATTTT4-1-1-7-1-2-4 AAAAtCtcaactaCcaTTTT 609_6 -20.75 25249 609AAAATCTCAACTACCATTTT 1-1-1-2-1-8-1-1-4 AaAatCtcaactacCaTTTT 609_7 -19.3025249 609 AAAATCTCAACTACCATTTT 1-2-3-7-1-1-1-1-3 AaaATCtcaactaCcAtTTT609_8 -20.51 25249 609 AAAATCTCAACTACCATTTT 2-2-2-10-1-1-2AAaaTCtcaactaccaTtTT 609_9 -18.72 25249 610 AAAATCTCAACTACCATTT1-4-1-6-4-1-2 AaaatCtcaactACCAtTT 610_1 -20.63 25250 610AAAATCTCAACTACCATTT 3-10-6 AAAatctcaactaCCATTT 610_2 -21.90 25250 610AAAATCTCAACTACCATTT 6-6-2-2-3 AAAATCtcaactACcaTTT 610_3 -21.46 25250 610AAAATCTCAACTACCATTT 2-2-2-7-2-1-3 AAaaTCtcaactaCCaTTT 610_4 -21.18 25250610 AAAATCTCAACTACCATTT 6-7-2-2-2 AAAATCtcaactaCCatTT 610_5 -22.10 25250610 AAAATCTCAACTACCATTT 2-1-1-1-1-8-5 AAaAtCtcaactacCATTT 610_6 -20.2725250 610 AAAATCTCAACTACCATTT 1-1-1-1-2-8-5 AaAaTCtcaactacCATTT 610_7-20.88 25250 610 AAAATCTCAACTACCATTT 1-1-2-1-1-8-2-1-2AaAAtCtcaactacCAtTT 610_8 -18.51 25250 610 AAAATCTCAACTACCATTT 6-9-4AAAATCtcaactaccATTT 610_9 -20.94 25250 611 GAAAATCTCAACTACCATT1-1-3-7-1-2-4 GaAAAtctcaacTacCATT 611_1 -20.48 25251 611GAAAATCTCAACTACCATT 1-1-2-8-1-1-1-1-3 GaAAatctcaacTaCcATT 611_2 -18.7525251 611 GAAAATCTCAACTACCATT 3-1-1-10-4 GAAaAtctcaactacCATT 611_3-20.73 25251 611 GAAAATCTCAACTACCATT 2-1-2-10-4 GAaAAtctcaactacCATT611_4 -20.73 25251 611 GAAAATCTCAACTACCATT 2-2-1-7-1-4-2GAaaAtctcaacTaccaTT 611_5 -18.28 25251 611 GAAAATCTCAACTACCATT 2-12-5GAaaatctcaactaCCATT 611_6 -22.25 25251 611 GAAAATCTCAACTACCATT4-10-2-1-2 GAAAatctcaactaCCaTT 611_7 -21.06 25251 611GAAAATCTCAACTACCATT 4-10-1-1-3 GAAAatctcaactaCcATT 611_8 -19.73 25251611 GAAAATCTCAACTACCATT 5-12-2 GAAAAtctcaactaccaTT 611_9 -18.61 25251612 TGAAAATCTCAACTACCAT 1-4-1-6-1-1-2-1-2 TgaaaAtctcaaCtACcAT 612_1-18.43 25252 612 TGAAAATCTCAACTACCAT 2-1-2-7-1-2-1-1-2TGaAAatctcaaCtaCcAT 612_2 -19.46 25252 612 TGAAAATCTCAACTACCAT1-1-2-8-1-2-1-1-2 TgAAaatctcaaCtaCcAT 612_3 -18.58 25252 612TGAAAATCTCAACTACCAT 1-2-1-1-1-6-1-3-3 TgaAaAtctcaaCtacCAT 612_4 -19.4025252 612 TGAAAATCTCAACTACCAT 1-3-2-10-3 TgaaAAtctcaactacCAT 612_5-18.60 25252 612 TGAAAATCTCAACTACCAT 1-11-1-2-4 TgaaaatctcaaCtaCCAT612_6 -21.11 25252 612 TGAAAATCTCAACTACCAT 3-1-2-6-1-4-2TGAaAAtctcaaCtaccAT 612_7 -20.39 25252 612 TGAAAATCTCAACTACCAT1-1-1-1-1-7-1-3-3 TgAaAatctcaaCtacCAT 612_8 -19.60 25252 612TGAAAATCTCAACTACCAT 4-12-3 TGAAaatctcaactacCAT 612_9 -21.07 25252 613ATCATTCTCAACAATTAAA 4-8-7 ATCAttctcaacAATTAAA 613_1 -20.89 30599 613ATCATTCTCAACAATTAAA 1-1-4-6-7 AtCATTctcaacAATTAAA 613_2 -21.09 30599 613ATCATTCTCAACAATTAAA 5-7-2-1-1-1-2 ATCATtctcaacAAtTaAA 613_3 -19.03 30599613 ATCATTCTCAACAATTAAA 5-8-2-2-2 ATCATtctcaacaATtaAA 613_4 -19.28 30599613 ATCATTCTCAACAATTAAA 4-1-1-8-5 ATCAtTctcaacaaTTAAA 613_5 -19.86 30599613 ATCATTCTCAACAATTAAA 5-7-4-1-2 ATCATtctcaacAATTaAA 613_6 -20.79 30599613 ATCATTCTCAACAATTAAA 4-8-1-1-5 ATCAttctcaacAaTTAAA 613_7 -19.56 30599613 ATCATTCTCAACAATTAAA 1-1-4-6-1-1-5 AtCATTctcaacAaTTAAA 613_8 -19.7630599 613 ATCATTCTCAACAATTAAA 4-1-1-7-3-1-2 ATCAtTctcaacaATTaAA 613_9-19.64 30599 613 ATCATTCTCAACAATTAAA 5-8-1-1-4 ATCATtctcaacaAtTAAA613_10 -20.11 30599 614 ATCATTCTCAACAATTAA 4-8-6 ATCAttctcaacAATTAA614_1 -20.14 30600 614 ATCATTCTCAACAATTAA 1-1-4-6-6 AtCATTctcaacAATTAA614_2 -20.34 30600 614 ATCATTCTCAACAATTAA 5-8-1-1-3 ATCATtctcaacaAtTAA614_3 -19.36 30600 614 ATCATTCTCAACAATTAA 4-8-1-1-4 ATCAttctcaacAaTTAA614_4 -18.81 30600 614 ATCATTCTCAACAATTAA 5-8-5 ATCATtctcaacaATTAA 614_5-21.12 30600 614 ATCATTCTCAACAATTAA 5-7-1-2-3 ATCATtctcaacAatTAA 614_6-19.11 30600 614 ATCATTCTCAACAATTAA 3-10-5 ATCattctcaacaATTAA 614_7-18.40 30600 614 ATCATTCTCAACAATTAA 4-9-1-1-3 ATCAttctcaacaAtTAA 614_8-18.11 30600 614 ATCATTCTCAACAATTAA 4-1-1-8-4 ATCAtTctcaacaaTTAA 614_9-19.11 30600 614 ATCATTCTCAACAATTAA 1-1-3-9-4 AtCATtctcaacaaTTAA 614_10-18.05 30600 615 GATCATTCTCAACAATTAA 2-3-1-6-2-1-4 GAtcaTtctcaaCAaTTAA615_1 -20.54 30600 615 GATCATTCTCAACAATTAA 1-2-2-7-1-2-4GatCAttctcaaCaaTTAA 615_2 -19.04 30600 615 GATCATTCTCAACAATTAA2-1-3-6-3-2-2 GAtCATtctcaaCAAttAA 615_3 -21.29 30600 615GATCATTCTCAACAATTAA 2-1-2-8-2-1-3 GAtCAttctcaacAAtTAA 615_4 -19.70 30600615 GATCATTCTCAACAATTAA 5-8-1-1-1-1-2 GATCAttctcaacAaTtAA 615_5 -19.7930600 615 GATCATTCTCAACAATTAA 4-8-3-2-2 GATCattctcaaCAAttAA 615_6 -20.5030600 615 GATCATTCTCAACAATTAA 1-2-3-6-2-2-3 GatCATtctcaaCAatTAA 615_7-20.82 30600 615 GATCATTCTCAACAATTAA 2-2-2-6-1-1-5 GAtcATtctcaaCaATTAA615_8 -21.04 30600 615 GATCATTCTCAACAATTAA 2-1-1-8-1-2-4GAtCattctcaaCaaTTAA 615_9 -19.28 30600 615 GATCATTCTCAACAATTAA1-1-3-9-1-1-3 GaTCAttctcaacaAtTAA 615_10 -18.85 30600 616AGATCATTCTCAACAATTA 1-1-1-2-1-7-3-1-2 AgAtcAttctcaaCAAtTA 616_1 -19.1030601 616 AGATCATTCTCAACAATTA 1-3-1-8-2-1-3 AgatCattctcaaCAaTTA 616_2-19.65 30601 616 AGATCATTCTCAACAATTA 1-3-2-6-1-1-1-2-2AgatCAttctcaAcAatTA 616_3 -18.49 30601 616 AGATCATTCTCAACAATTA1-1-1-1-2-11-2 AgAtCAttctcaacaatTA 616_4 -18.49 30601 616AGATCATTCTCAACAATTA 1-1-1-2-1-9-4 AgAtcAttctcaacaATTA 616_5 -18.49 30601616 AGATCATTCTCAACAATTA 1-3-2-6-1-1-5 AgatCAttctcaAcAATTA 616_6 -20.7630601 616 AGATCATTCTCAACAATTA 2-2-1-8-3-1-2 AGatCattctcaaCAAtTA 616_7-20.47 30601 616 AGATCATTCTCAACAATTA 3-2-1-7-1-2-3 AGAtcAttctcaaCaaTTA616_8 -20.51 30601 616 AGATCATTCTCAACAATTA 1-2-3-7-1-3-2AgaTCAttctcaaCaatTA 616_9 -19.80 30601 616 AGATCATTCTCAACAATTA1-1-1-1-2-8-2-1-2 AgAtCAttctcaacAAtTA 616_10 -19.08 30601 617GATCATTCTCAACAATTA 2-3-1-6-6 GAtcaTtctcaaCAATTA 617_1 -21.11 30601 617GATCATTCTCAACAATTA 2-1-2-8-5 GAtCAttctcaacAATTA 617_2 -20.71 30601 617GATCATTCTCAACAATTA 2-2-2-6-2-2-2 GAtcATtctcaaCAatTA 617_3 -19.70 30601617 GATCATTCTCAACAATTA 1-1-3-7-1-1-1-1-2 GaTCAttctcaaCaAtTA 617_4 -18.7830601 617 GATCATTCTCAACAATTA 2-1-2-10-3 GAtCAttctcaacaaTTA 617_5 -19.3130601 617 GATCATTCTCAACAATTA 2-1-1-1-1-6-3-1-2 GAtCaTtctcaaCAAtTA 617_6-20.02 30601 617 GATCATTCTCAACAATTA 2-1-2-7-2-2-2 GAtCAttctcaaCAatTA617_7 -20.53 30601 617 GATCATTCTCAACAATTA 2-1-3-6-1-2-3GAtCATtctcaaCaaTTA 617_8 -21.24 30601 617 GATCATTCTCAACAATTA 2-2-1-8-5GAtcAttctcaacAATTA 617_9 -18.63 30601 617 GATCATTCTCAACAATTA1-1-3-9-1-1-2 GaTCAttctcaacaAtTA 617_10 -18.10 30601 618AGATCATTCTCAACAATT 1-3-2-6-6 AgatCAttctcaACAATT 618_1 -21.03 30602 618AGATCATTCTCAACAATT 1-1-1-1-2-7-5 AgAtCAttctcaaCAATT 618_2 -20.70 30602618 AGATCATTCTCAACAATT 1-1-4-6-1-3-2 AgATCAttctcaAcaaTT 618_3 -19.5630602 618 AGATCATTCTCAACAATT 3-1-1-9-4 AGAtCattctcaacAATT 618_4 -19.6130602 618 AGATCATTCTCAACAATT 2-1-3-10-2 AGaTCAttctcaacaaTT 618_5 -19.0930602 618 AGATCATTCTCAACAATT 1-2-3-6-1-3-2 AgaTCAttctcaAcaaTT 618_6-18.25 30602 618 AGATCATTCTCAACAATT 2-2-2-7-2-1-2 AGatCAttctcaaCAaTT618_7 -20.14 30602 618 AGATCATTCTCAACAATT 1-1-1-1-2-7-1-1-3AgAtCAttctcaaCaATT 618_8 -19.02 30602 618 AGATCATTCTCAACAATT 1-2-3-8-4AgaTCAttctcaacAATT 618_9 -19.23 30602 618 AGATCATTCTCAACAATT 3-1-1-10-3AGAtCattctcaacaATT 618_10 -19.34 30602 619 GATCATTCTCAACAATT 2-1-2-6-6GAtCAttctcaACAATT 619_1 -21.40 30602 619 GATCATTCTCAACAATT 1-1-3-7-5GaTCAttctcaaCAATT 619_2 -19.99 30602 619 GATCATTCTCAACAATT 5-7-1-2-2GATCAttctcaaCaaTT 619_3 -19.69 30602 619 GATCATTCTCAACAATT 5-6-1-1-4GATCAttctcaAcAATT 619_4 -20.83 30602 619 GATCATTCTCAACAATT 2-1-2-7-5GAtCAttctcaaCAATT 619_5 -20.57 30602 619 GATCATTCTCAACAATT 5-6-1-3-2GATCAttctcaAcaaTT 619_6 -19.43 30602 619 GATCATTCTCAACAATT 4-8-5GATCattctcaaCAATT 619_7 -21.04 30602 619 GATCATTCTCAACAATT 1-1-3-7-2-1-2GaTCAttctcaaCAaTT 619_8 -18.67 30602 619 GATCATTCTCAACAATT 5-7-1-1-3GATCAttctcaaCaATT 619_9 -20.82 30602 619 GATCATTCTCAACAATT 2-1-2-8-4GAtCAttctcaacAATT 619_10 -18.48 30602 620 AAGATCATTCTCAACAAT4-1-1-6-1-1-4 AAGAtCattctcAaCAAT 620_1 -20.71 30603 620AAGATCATTCTCAACAAT 4-9-5 AAGAtcattctcaACAAT 620_2 -20.79 30603 620AAGATCATTCTCAACAAT 2-2-2-6-6 AAgaTCattctcAACAAT 620_3 -19.88 30603 620AAGATCATTCTCAACAAT 4-1-1-7-2-1-2 AAGAtCattctcaACaAT 620_4 -19.77 30603620 AAGATCATTCTCAACAAT 2-1-3-8-4 AAgATCattctcaaCAAT 620_5 -20.10 30603620 AAGATCATTCTCAACAAT 4-1-1-6-2-2-2 AAGAtCattctcAAcaAT 620_6 -18.9630603 620 AAGATCATTCTCAACAAT 3-1-2-6-1-1-4 AAGaTCattctcAaCAAT 620_7-20.12 30603 620 AAGATCATTCTCAACAAT 2-1-3-6-1-1-4 AAgATCattctcAaCAAT620_8 -20.17 30603 620 AAGATCATTCTCAACAAT 1-1-1-2-1-7-5AaGatCattctcaACAAT 620_9 -18.21 30603 620 AAGATCATTCTCAACAAT 4-1-1-8-4AAGAtCattctcaaCAAT 620_10 -20.63 30603 621 AAAGATCATTCTCAACAA 1-1-1-9-6AaAgatcattctCAACAA 621_1 -18.13 30604 621 AAAGATCATTCTCAACAA1-1-3-7-2-1-3 AaAGAtcattctCAaCAA 621_2 -20.08 30604 621AAAGATCATTCTCAACAA 1-3-2-6-2-1-3 AaagATcattctCAaCAA 621_3 -18.11 30604621 AAAGATCATTCTCAACAA 1-2-2-7-1-1-4 AaaGAtcattctCaACAA 621_4 -18.0730604 621 AAAGATCATTCTCAACAA 5-10-3 AAAGAtcattctcaaCAA 621_5 -18.6530604 621 AAAGATCATTCTCAACAA 1-1-3-7-3-1-2 AaAGAtcattctCAAcAA 621_6-18.59 30604 621 AAAGATCATTCTCAACAA 4-8-2-1-3 AAAGatcattctCAaCAA 621_7-19.10 30604 621 AAAGATCATTCTCAACAA 3-1-1-7-2-1-3 AAAgAtcattctCAaCAA621_8 -18.35 30604 621 AAAGATCATTCTCAACAA 1-1-2-8-2-1-3AaAGatcattctCAaCAA 621_9 -18.37 30604 621 AAAGATCATTCTCAACAA1-2-2-7-2-1-3 AaaGAtcattctCAaCAA 621_10 -18.74 30604 621AAAGATCATTCTCAACAA 5-7-1-2-3 AAAGAtcattctCaaCAA 621_11 -19.32 30604 622CAAAGATCATTCTCAACA 1-1-2-8-6 CaAAgatcattcTCAACA 622_1 -20.93 30605 622CAAAGATCATTCTCAACA 2-1-1-9-5 CAaAgatcattctCAACA 622_2 -20.68 30605 622CAAAGATCATTCTCAACA 1-4-1-7-5 CaaagAtcattctCAACA 622_3 -18.86 30605 622CAAAGATCATTCTCAACA 4-1-1-7-1-2-2 CAAAgAtcattctCaaCA 622_4 -19.40 30605622 CAAAGATCATTCTCAACA 3-1-2-10-2 CAAaGAtcattctcaaCA 622_5 -19.67 30605622 CAAAGATCATTCTCAACA 4-8-2-2-2 CAAAgatcattcTCaaCA 622_6 -20.10 30605622 CAAAGATCATTCTCAACA 1-1-2-1-1-7-5 CaAAgAtcattctCAACA 622_7 -20.2330605 622 CAAAGATCATTCTCAACA 2-1-1-9-2-1-2 CAaAgatcattctCAaCA 622_8-19.66 30605 622 CAAAGATCATTCTCAACA 3-2-1-7-1-1-3 CAAagAtcattctCaACA622_9 -19.21 30605 622 CAAAGATCATTCTCAACA 1-3-2-7-1-2-2CaaaGAtcattctCaaCA 622_10 -18.30 30605 623 CAAAGATCATTCTCAAC 3-8-6CAAagatcattCTCAAC 623_1 -19.95 30606 623 CAAAGATCATTCTCAAC 2-1-1-7-6CAaAgatcattCTCAAC 623_2 -20.23 30606 623 CAAAGATCATTCTCAAC 2-2-1-6-6CAaaGatcattCTCAAC 623_3 -20.15 30606 623 CAAAGATCATTCTCAAC 1-2-2-6-6CaaAGatcattCTCAAC 623_4 -20.00 30606 623 CAAAGATCATTCTCAAC 5-6-1-1-4CAAAGatcattCtCAAC 623_5 -20.35 30606 623 CAAAGATCATTCTCAAC 4-7-3-1-2CAAAgatcattCTCaAC 623_6 -19.28 30606 623 CAAAGATCATTCTCAAC 3-1-1-6-1-1-4CAAaGatcattCtCAAC 623_7 -18.81 30606 623 CAAAGATCATTCTCAAC 2-1-1-7-1-1-4CAaAgatcattCtCAAC 623_8 -18.36 30606 623 CAAAGATCATTCTCAAC 1-2-2-6-1-1-4CaaAGatcattCtCAAC 623_9 -18.12 30606 623 CAAAGATCATTCTCAAC 4-8-5CAAAgatcattcTCAAC 623_10 -19.31 30606 624 CTCAAAGATCATTCTCA 1-2-1-7-6CtcAaagatcaTTCTCA 624_1 -20.57 30608 624 CTCAAAGATCATTCTCA1-1-1-1-1-7-2-1-2 CtCaAagatcatTCtCA 624_2 -18.69 30608 624CTCAAAGATCATTCTCA 1-1-2-7-1-2-3 CtCAaagatcaTtcTCA 624_3 -19.51 30608 624CTCAAAGATCATTCTCA 3-10-1-1-2 CTCaaagatcattCtCA 624_4 -19.23 30608 624CTCAAAGATCATTCTCA 1-1-3-8-4 CtCAAagatcattCTCA 624_5 -21.26 30608 624CTCAAAGATCATTCTCA 1-1-3-6-1-1-1-1-2 CtCAAagatcaTtCtCA 624_6 -19.82 30608624 CTCAAAGATCATTCTCA 4-7-1-3-2 CTCAaagatcaTtctCA 624_7 -20.18 30608 624CTCAAAGATCATTCTCA 1-2-2-7-5 CtcAAagatcatTCTCA 624_8 -20.16 30608 624CTCAAAGATCATTCTCA 1-1-2-8-2-1-2 CtCAaagatcatTCtCA 624_9 -19.83 30608 624CTCAAAGATCATTCTCA 3-10-4 CTCaaagatcattCTCA 624_10 -21.11 30608 625TACACTTAATTATACTTCCA 1-2-1-1-1-7-2-3-2 TacAcTtaattatACttcCA 625_1 -20.3330666 625 TACACTTAATTATACTTCCA 1-2-1-2-1-6-1-4-2 TacActTaattatActtcCA625_2 -19.15 30666 625 TACACTTAATTATACTTCCA 1-4-1-7-1-1-1-2-2TacacTtaattatAcTtcCA 625_3 -19.30 30666 625 TACACTTAATTATACTTCCA1-1-1-2-2-6-1-4-2 TaCacTTaattatActtcCA 625_4 -20.71 30666 625TACACTTAATTATACTTCCA 1-1-1-3-1-8-1-2-2 TaCactTaattatacTtcCA 625_5 -20.0030666 625 TACACTTAATTATACTTCCA 1-2-1-1-2-8-1-2-2 TacAcTTaattatacTtcCA625_6 -20.50 30666 625 TACACTTAATTATACTTCCA 1-2-1-13-3TacActtaattatacttCCA 625_7 -20.60 30666 625 TACACTTAATTATACTTCCA1-4-1-11-3 TacacTtaattatacttCCA 625_8 -20.96 30666 625TACACTTAATTATACTTCCA 2-1-1-1-1-12-2 TAcAcTtaattatacttcCA 625_9 -19.9730666 625 TACACTTAATTATACTTCCA 1-1-1-2-1-7-2-3-2 TaCacTtaattatACttcCA625_10 -20.87 30666 625 TACACTTAATTATACTTCCA 1-2-1-1-2-6-1-1-1-2-2TacAcTTaattatAcTtcCA 625_11 -20.69 30666 625 TACACTTAATTATACTTCCA1-2-1-1-1-9-1-1-3 TacAcTtaattatacTtCCA 625_12 -21.63 30666 625TACACTTAATTATACTTCCA 1-1-1-3-1-10-3 TaCactTaattatacttCCA 625_13 -21.8630666 625 TACACTTAATTATACTTCCA 2-1-2-1-1-11-2 TAcACtTaattatacttcCA625_14 -21.58 30666 626 TTACACTTAATTATACTTCC 1-3-1-1-1-7-2-2-2TtacAcTtaattatACttCC 626_1 -19.98 30667 626 TTACACTTAATTATACTTCC1-5-1-7-1-1-1-1-2 TtacacTtaattatAcTtCC 626_2 -18.96 30667 626TTACACTTAATTATACTTCC 2-4-1-11-2 TTacacTtaattatacttCC 626_3 -19.49 30667626 TTACACTTAATTATACTTCC 1-5-1-9-4 TtacacTtaattatacTTCC 626_4 -20.2630667 626 TTACACTTAATTATACTTCC 1-1-1-3-1-8-1-2-2 TtAcacTtaattataCttCC626_5 -19.43 30667 626 TTACACTTAATTATACTTCC 1-1-2-2-1-7-1-3-2TtACacTtaattatActtCC 626_6 -19.72 30667 626 TTACACTTAATTATACTTCC3-1-1-12-3 TTAcActtaattatactTCC 626_7 -21.33 30667 626TTACACTTAATTATACTTCC 1-1-1-1-1-1-1-9-1-1-2 TtAcAcTtaattatacTtCC 626_8-19.10 30667 626 TTACACTTAATTATACTTCC 1-2-2-1-1-11-2TtaCAcTtaattatacttCC 626_9 -20.49 30667 626 TTACACTTAATTATACTTCC1-5-1-7-2-1-3 TtacacTtaattatACtTCC 626_10 -20.82 30667 626TTACACTTAATTATACTTCC 4-2-1-7-1-3-2 TTACacTtaattatActtCC 626_11 -21.9930667 626 TTACACTTAATTATACTTCC 1-1-1-1-3-8-1-2-2 TtAcACTtaattataCttCC626_12 -21.65 30667 626 TTACACTTAATTATACTTCC 2-1-2-11-4TTaCActtaattatacTTCC 626_13 -23.23 30667 626 TTACACTTAATTATACTTCC2-2-1-1-1-9-1-1-2 TTacAcTtaattatacTtCC 626_14 -20.15 30667 627TTTACACTTAATTATACTTC 2-1-2-8-1-1-5 TTTACacttaattAtACTTC 627_1 -20.0230668 627 TTTACACTTAATTATACTTC 2-3-1-7-4-1-2 TTtacActtaattATACtTC 627_2-19.89 30668 627 TTTACACTTAATTATACTTC 1-2-1-1-1-7-2-1-4TttAcActtaattATaCTTC 627_3 -19.35 30668 627 TTTACACTTAATTATACTTC1-1-3-8-3-2-2 TtTACacttaattATActTC 627_4 -20.58 30668 627TTTACACTTAATTATACTTC 3-2-1-7-3-1-3 TTTacActtaattATAcTTC 627_5 -20.7630668 627 TTTACACTTAATTATACTTC 1-3-2-7-2-2-3 TttaCActtaattATacTTC 627_6-19.58 30668 627 TTTACACTTAATTATACTTC 3-2-1-7-2-1-4 TTTacActtaattATaCTTC627_7 -21.21 30668 627 TTTACACTTAATTATACTTC 3-1-1-8-1-2-4TTTaCacttaattAtaCTTC 627_8 -20.07 30668 627 TTTACACTTAATTATACTTC6-7-1-4-2 TTTACActtaattAtactTC 627_9 -20.56 30668 627TTTACACTTAATTATACTTC 4-1-1-7-4-1-2 TTTAcActtaattATACtTC 627_10 -22.3630668 627 TTTACACTTAATTATACTTC 3-1-1-1-1-6-3-1-3 TTTaCaCttaattATAcTTC627_11 -22.29 30668 627 TTTACACTTAATTATACTTC 2-1-3-7-3-2-2TTTACActtaattATActTC 627_12 -21.19 30668 627 TTTACACTTAATTATACTTC3-1-2-7-2-1-4 TTTaCActtaattATaCTTC 627_13 -23.30 30668 627TTTACACTTAATTATACTTC 1-1-4-7-1-2-4 TtTACActtaattAtaCTTC 627_14 -21.9430668 628 ATTTACACTTAATTATACTT 2-1-1-2-1-6-3-1-3 ATtTacActtaatTATaCTT628_1 -21.21 30669 628 ATTTACACTTAATTATACTT 3-1-1-8-2-1-4ATTtAcacttaatTAtACTT 628_2 -20.27 30669 628 ATTTACACTTAATTATACTT1-1-2-2-1-6-4-1-2 AtTTacActtaatTATAcTT 628_3 -20.33 30669 628ATTTACACTTAATTATACTT 1-3-1-1-1-7-6 AtttAcActtaattATACTT 628_4 -19.3030669 628 ATTTACACTTAATTATACTT 2-2-2-7-3-2-2 ATttACacttaatTATacTT 628_5-19.94 30669 628 ATTTACACTTAATTATACTT 4-1-2-6-2-3-2 ATTTaCActtaatTAtacTT628_6 -21.29 30669 628 ATTTACACTTAATTATACTT 1-1-4-7-1-1-1-2-2AtTTACacttaatTaTacTT 628_7 -19.33 30669 628 ATTTACACTTAATTATACTT2-2-3-6-1-2-4 ATttACActtaatTatACTT 628_8 -20.97 30669 628ATTTACACTTAATTATACTT 4-2-1-6-1-3-3 ATTTacActtaatTataCTT 628_9 -19.7330669 628 ATTTACACTTAATTATACTT 1-1-2-1-2-6-4-1-2 AtTTaCActtaatTATAcTT628_10 -22.43 30669 628 ATTTACACTTAATTATACTT 3-2-2-6-2-2-3ATTtaCActtaatTAtaCTT 628_11 -21.72 30669 628 ATTTACACTTAATTATACTT1-2-4-6-2-2-3 AttTACActtaatTAtaCTT 628_12 -22.02 30669 628ATTTACACTTAATTATACTT 2-1-1-1-2-6-1-1-5 ATtTaCActtaatTaTACTT 628_13-23.00 30669 628 ATTTACACTTAATTATACTT 5-8-1-1-1-1-3 ATTTAcacttaatTaTaCTT628_14 -21.68 30669 629 TTCTACTATACTTTCCTCT 1-3-1-7-1-1-1-2-2TtctActatactTtCctCT 629_1 -21.04 30711 629 TTCTACTATACTTTCCTCT1-11-1-1-1-2-2 TtctactatactTtCctCT 629_2 -20.85 30711 629TTCTACTATACTTTCCTCT 1-11-1-2-1-1-2 TtctactatactTtcCtCT 629_3 -20.9730711 629 TTCTACTATACTTTCCTCT 1-1-1-9-1-4-2 TtCtactatactTtcctCT 629_4-21.06 30711 629 TTCTACTATACTTTCCTCT 1-1-1-11-1-2-2 TtCtactatactttCctCT629_5 -21.53 30711 629 TTCTACTATACTTTCCTCT 1-3-1-9-1-2-2TtctActatactttCctCT 629_6 -20.74 30711 629 TTCTACTATACTTTCCTCT1-4-1-8-1-2-2 TtctaCtatactttCctCT 629_7 -21.54 30711 629TTCTACTATACTTTCCTCT 1-13-1-2-2 TtctactatactttCctCT 629_8 -20.55 30711629 TTCTACTATACTTTCCTCT 1-1-1-12-1-1-2 TtCtactatactttcCtCT 629_9 -21.6530711 629 TTCTACTATACTTTCCTCT 1-3-1-10-1-1-2 TtctActatactttcCtCT 629_10-20.86 30711 629 TTCTACTATACTTTCCTCT 1-14-1-1-2 TtctactatactttcCtCT629_11 -20.67 30711 629 TTCTACTATACTTTCCTCT 1-1-1-1-1-7-1-1-1-2-2TtCtActatactTtCctCT 629_12 -22.02 30711 629 TTCTACTATACTTTCCTCT1-1-1-2-1-8-1-2-2 TtCtaCtatactttCctCT 629_13 -22.52 30711 629TTCTACTATACTTTCCTCT 1-3-2-8-1-2-2 TtctACtatactttCctCT 629_14 -22.1430711 629 TTCTACTATACTTTCCTCT 1-1-1-1-1-10-1-1-2 TtCtActatactttcCtCT629_15 -21.84 30711 629 TTCTACTATACTTTCCTCT 1-1-1-2-1-9-1-1-2TtCtaCtatactttcCtCT 629_16 -22.64 30711 630 GTTCTACTATACTTTCCTC1-12-1-1-1-1-2 GttctactatactTtCcTC 630_1 -20.78 30712 630GTTCTACTATACTTTCCTC 1-4-1-9-1-1-2 GttctActatactttCcTC 630_2 -20.67 30712630 GTTCTACTATACTTTCCTC 1-14-1-1-2 GttctactatactttCcTC 630_3 -20.4830712 631 GTTCTACTATACTTTCCT 1-2-1-1-1-7-1-2-2 GttCtActatactTtcCT 631_1-20.25 30713 631 GTTCTACTATACTTTCCT 1-2-1-9-1-2-2 GttCtactatactTtcCT631_2 -20.06 30713 631 GTTCTACTATACTTTCCT 1-2-1-11-3 GttCtactatactttCCT631_3 -22.13 30713 631 GTTCTACTATACTTTCCT 1-4-1-9-3 GttctActatactttCCT631_4 -21.34 30713 631 GTTCTACTATACTTTCCT 1-14-3 GttctactatactttCCT631_5 -21.15 30713 631 GTTCTACTATACTTTCCT 2-1-1-1-1-10-2GTtCtActatactttcCT 631_6 -21.50 30713 631 GTTCTACTATACTTTCCT 2-1-1-12-2GTtCtactatactttcCT 631_7 -21.30 30713 631 GTTCTACTATACTTTCCT1-2-1-1-1-10-2 GttCtActatactttcCT 631_8 -19.95 30713 631GTTCTACTATACTTTCCT 1-2-1-12-2 GttCtactatactttcCT 631_9 -19.76 30713 631GTTCTACTATACTTTCCT 1-15-2 GttctactatactttcCT 631_10 -18.78 30713 631GTTCTACTATACTTTCCT 1-2-1-9-1-1-3 GttCtactatactTtCCT 631_11 -22.43 30713631 GTTCTACTATACTTTCCT 2-1-1-1-1-7-1-2-2 GTtCtActatactTtcCT 631_12-21.80 30713 631 GTTCTACTATACTTTCCT 1-2-2-8-1-2-2 GttCTactatactTtcCT631_13 -21.68 30713 631 GTTCTACTATACTTTCCT 1-2-1-1-1-9-3GttCtActatactttCCT 631_14 -22.32 30713 631 GTTCTACTATACTTTCCT 1-2-3-10-2GttCTActatactttcCT 631_15 -22.60 30713 632 AGTTCTACTATACTTTCC 1-12-1-2-2AgttctactatacTttCC 632_1 -19.37 30714 632 AGTTCTACTATACTTTCC 1-13-1-1-2AgttctactatactTtCC 632_2 -19.16 30714 632 AGTTCTACTATACTTTCC 1-1-1-13-2AgTtctactatactttCC 632_3 -19.51 30714 632 AGTTCTACTATACTTTCC 1-15-2AgttctactatactttCC 632_4 -18.86 30714 632 AGTTCTACTATACTTTCC1-1-1-10-1-2-2 AgTtctactatacTttCC 632_5 -20.03 30714 632AGTTCTACTATACTTTCC 1-4-1-7-1-2-2 AgttcTactatacTttCC 632_6 -20.31 30714632 AGTTCTACTATACTTTCC 2-14-2 AGttctactatactttCC 632_7 -20.26 30714 632AGTTCTACTATACTTTCC 1-2-1-12-2 AgtTctactatactttCC 632_8 -19.23 30714 632AGTTCTACTATACTTTCC 1-4-1-10-2 AgttcTactatactttCC 632_9 -19.80 30714 632AGTTCTACTATACTTTCC 2-10-1-3-2 AGttctactataCtttCC 632_10 -21.25 30714 632AGTTCTACTATACTTTCC 1-4-1-6-1-3-2 AgttcTactataCtttCC 632_11 -20.79 30714632 AGTTCTACTATACTTTCC 1-4-1-7-2-1-2 AgttcTactatacTTtCC 632_12 -21.1330714 632 AGTTCTACTATACTTTCC 1-1-1-11-1-1-2 AgTtctactatactTtCC 632_13-19.82 30714 632 AGTTCTACTATACTTTCC 1-3-1-11-2 AgttCtactatactttCC 632_14-19.83 30714 633 CAACATTATTAACCACCTTA 1-13-3-1-2 CaacattattaaccACCtTA633_1 -22.44 33376 633 CAACATTATTAACCACCTTA 4-10-1-2-3CAACattattaaccAccTTA 633_2 -22.98 33376 633 CAACATTATTAACCACCTTA2-2-1-10-1-1-3 CAacAttattaaccaCcTTA 633_3 -21.97 33376 633CAACATTATTAACCACCTTA 1-4-2-8-1-2-2 CaacaTTattaaccaCctTA 633_4 -21.0833376 633 CAACATTATTAACCACCTTA 1-1-2-11-1-2-2 CaACattattaaccaCctTA 633_5-20.90 33376 633 CAACATTATTAACCACCTTA 1-2-2-13-2 CaaCAttattaaccacctTA633_6 -20.76 33376 633 CAACATTATTAACCACCTTA 1-1-1-1-1-11-1-1-2CaAcAttattaaccacCtTA 633_7 -19.97 33376 633 CAACATTATTAACCACCTTA 1-15-4CaacattattaaccacCTTA 633_8 -21.21 33376 633 CAACATTATTAACCACCTTA2-4-1-11-2 CAacatTattaaccacctTA 633_9 -20.83 33376 634CAACATTATTAACCACCTT 2-10-2-3-2 CAacattattaaCCaccTT 634_1 -21.86 33377634 CAACATTATTAACCACCTT 1-14-4 CaacattattaaccaCCTT 634_2 -21.36 33377634 CAACATTATTAACCACCTT 1-1-1-11-1-1-3 CaAcattattaaccAcCTT 634_3 -19.5433377 634 CAACATTATTAACCACCTT 3-1-1-11-3 CAAcAttattaaccacCTT 634_4-21.13 33377 634 CAACATTATTAACCACCTT 3-11-2-1-2 CAAcattattaaccACcTT634_5 -20.84 33377 634 CAACATTATTAACCACCTT 2-1-2-9-1-1-3CAaCAttattaaccAcCTT 634_6 -22.76 33377 634 CAACATTATTAACCACCTT2-1-2-10-1-1-2 CAaCAttattaaccaCcTT 634_7 -21.83 33377 634CAACATTATTAACCACCTT 1-1-2-11-1-1-2 CaACattattaaccaCcTT 634_8 -19.7033377 634 CAACATTATTAACCACCTT 1-2-1-12-3 CaaCattattaaccacCTT 634_9-19.66 33377 635 GCAACATTATTAACCACCT 1-1-1-2-1-6-2-3-2GcAacAttattaACcacCT 635_1 -21.56 33378 635 GCAACATTATTAACCACCT1-1-2-1-1-6-1-2-1-1-2 GcAAcAttattaAccAcCT 635_2 -21.14 33378 635GCAACATTATTAACCACCT 1-11-2-1-1-1-2 GcaacattattaACcAcCT 635_3 -21.5933378 635 GCAACATTATTAACCACCT 1-4-1-6-1-3-3 GcaacAttattaAccaCCT 635_4-22.69 33378 635 GCAACATTATTAACCACCT 1-1-1-1-1-7-1-4-2GcAaCattattaAccacCT 635_5 -21.01 33378 635 GCAACATTATTAACCACCT1-11-1-1-1-2-2 GcaacattattaAcCacCT 635_6 -20.83 33378 635GCAACATTATTAACCACCT 2-3-1-6-1-4-2 GCaacAttattaAccacCT 635_7 -22.63 33378635 GCAACATTATTAACCACCT 1-1-1-12-1-1-2 GcAacattattaaccAcCT 635_8 -20.0533378 635 GCAACATTATTAACCACCT 1-2-1-1-1-11-2 GcaAcAttattaaccacCT 635_9-20.30 33378 636 AGCAACATTATTAACCACC 1-2-1-9-2-1-3 AgcAacattattaACcACC636_1 -22.13 33379 636 AGCAACATTATTAACCACC 1-11-1-1-1-2-2AgcaacattattAaCcaCC 636_2 -20.80 33379 636 AGCAACATTATTAACCACC1-4-1-6-2-3-2 AgcaaCattattAAccaCC 636_3 -21.32 33379 636AGCAACATTATTAACCACC 1-2-2-7-1-2-1-1-2 AgcAAcattattAacCaCC 636_4 -21.2933379 636 AGCAACATTATTAACCACC 2-11-1-3-2 AGcaacattattaAccaCC 636_5-21.75 33379 636 AGCAACATTATTAACCACC 1-1-1-1-1-8-1-2-3AgCaAcattattaAccACC 636_6 -22.16 33379 636 AGCAACATTATTAACCACC1-2-1-1-1-6-1-3-3 AgcAaCattattAaccACC 636_7 -21.33 33379 636AGCAACATTATTAACCACC 2-1-2-12-2 AGcAAcattattaaccaCC 636_8 -22.02 33379636 AGCAACATTATTAACCACC 1-15-3 AgcaacattattaaccACC 636_9 -20.45 33379637 AGCAACATTATTAACCAC 2-1-1-9-5 AGcAacattattaACCAC 637_1 -21.97 33380637 AGCAACATTATTAACCAC 1-3-1-7-6 AgcaAcattattAACCAC 637_2 -21.20 33380637 AGCAACATTATTAACCAC 2-10-2-1-3 AGcaacattattAAcCAC 637_3 -19.42 33380637 AGCAACATTATTAACCAC 1-2-1-8-1-1-4 AgcAacattattAaCCAC 637_4 -19.8433380 637 AGCAACATTATTAACCAC 3-9-3-1-2 AGCaacattattAACcAC 637_5 -20.9433380 637 AGCAACATTATTAACCAC 1-1-3-7-3-1-2 AgCAAcattattAACcAC 637_6-20.15 33380 637 AGCAACATTATTAACCAC 1-1-3-7-2-1-3 AgCAAcattattAAcCAC637_7 -20.96 33380 637 AGCAACATTATTAACCAC 5-7-1-3-2 AGCAAcattattAaccAC637_8 -21.24 33380 637 AGCAACATTATTAACCAC 3-1-1-8-1-2-2AGCaAcattattaAccAC 637_9 -19.86 33380 638 GTTTCCATCTACTATTAAT1-3-1-7-1-1-1-1-3 GtttCcatctacTaTtAAT 638_1 -19.59 39806 638GTTTCCATCTACTATTAAT 1-1-1-9-2-3-2 GtTtccatctacTAttaAT 638_2 -19.50 39806638 GTTTCCATCTACTATTAAT 1-4-1-6-2-2-3 GtttcCatctacTAttAAT 638_3 -20.0939806 638 GTTTCCATCTACTATTAAT 1-3-1-8-1-2-3 GtttCcatctactAttAAT 638_4-18.30 39806 638 GTTTCCATCTACTATTAAT 3-1-1-8-1-3-2 GTTtCcatctactAttaAT638_5 -20.35 39806 638 GTTTCCATCTACTATTAAT 1-2-2-12-2GttTCcatctactattaAT 638_6 -18.88 39806 638 GTTTCCATCTACTATTAAT1-1-1-11-1-1-3 GtTtccatctactaTtAAT 638_7 -18.18 39806 638GTTTCCATCTACTATTAAT 2-2-1-10-1-1-2 GTttCcatctactatTaAT 638_8 -20.1639806 638 GTTTCCATCTACTATTAAT 1-1-1-1-2-10-3 GtTtCCatctactattAAT 638_9-20.69 39806 638 GTTTCCATCTACTATTAAT 2-2-1-7-1-3-3 GTttCcatctacTattAAT638_10 -20.69 39806 638 GTTTCCATCTACTATTAAT 1-1-1-10-2-1-3GtTtccatctactATTAAT 638_11 -19.08 39806 638 GTTTCCATCTACTATTAAT1-3-1-8-1-1-1-1-2 GtttCcatctactAtTaAT 638_12 -18.72 39806 638GTTTCCATCTACTATTAAT 1-2-3-7-1-2-3 GttTCCatctactAttAAT 638_13 -21.4739806 638 GTTTCCATCTACTATTAAT 1-1-1-1-2-11-2 GtTtCCatctactattaAT 638_14-20.37 39806 639 GTTTCCATCTACTATTAA 1-11-2-1-3 GtttccatctacTAtTAA 639_1-19.21 39807 639 GTTTCCATCTACTATTAA 1-3-1-7-1-1-4 GtttCcatctacTaTTAA639_2 -19.80 39807 639 GTTTCCATCTACTATTAA 3-1-1-7-2-2-2GTTtCcatctacTAttAA 639_3 -20.57 39807 639 GTTTCCATCTACTATTAA2-2-1-7-1-1-1-1-2 GTttCcatctacTaTtAA 639_4 -19.07 39807 639GTTTCCATCTACTATTAA 1-3-2-7-2-1-2 GtttCCatctactATTAA 639_5 -19.67 39807639 GTTTCCATCTACTATTAA 3-2-1-6-1-3-2 GTTtcCatctacTattAA 639_6 -19.2539807 639 GTTTCCATCTACTATTAA 1-1-3-8-1-2-2 GtTTCcatctactAttAA 639_7-18.04 39807 639 GTTTCCATCTACTATTAA 1-1-1-1-2-10-2 GtTtCCatctactattAA639_8 -18.62 39807 639 GTTTCCATCTACTATTAA 3-1-1-9-4 GTTtCcatctactaTTAA639_9 -21.21 39807 639 GTTTCCATCTACTATTAA 1-3-2-6-2-2-2GtttCCatctacTAttAA 639_10 -20.39 39807 639 GTTTCCATCTACTATTAA1-1-3-7-1-1-1-1-2 GtTTCcatctacTaTtAA 639_11 -19.32 39807 639GTTTCCATCTACTATTAA 2-2-1-7-1-2-3 GTttCcatctacTatTAA 639_12 -20.39 39807639 GTTTCCATCTACTATTAA 2-2-1-8-2-1-2 GTttCcatctactATTAA 639_13 -19.0339807 639 GTTTCCATCTACTATTAA 1-1-1-1-2-8-4 GtTtCCatctactaTTAA 639_14-21.34 39807 640 TGTTTCCATCTACTATTA 1-1-1-11-1-1-2 TgTttccatctactAtTA640_1 -18.41 39808 640 TGTTTCCATCTACTATTA 1-2-1-9-2-1-2TgtTtccatctacTAtTA 640_2 -20.03 39808 640 TGTTTCCATCTACTATTA1-4-1-7-1-2-2 TgtttCcatctacTatTA 640_3 -19.37 39808 640TGTTTCCATCTACTATTA 1-4-1-8-4 TgtttCcatctactATTA 640_4 -20.28 39808 640TGTTTCCATCTACTATTA 1-4-1-8-1-1-2 TgtttCcatctactAtTA 640_5 -18.52 39808640 TGTTTCCATCTACTATTA 1-1-2-1-1-10-2 TgTTtCcatctactatTA 640_6 -19.8939808 640 TGTTTCCATCTACTATTA 1-4-1-9-3 TgtttCcatctactaTTA 640_7 -19.3739808 640 TGTTTCCATCTACTATTA 1-2-1-1-1-10-2 TgtTtCcatctactatTA 640_8-18.73 39808 640 TGTTTCCATCTACTATTA 1-4-1-10-2 TgtttCcatctactatTA 640_9-18.42 39808 640 TGTTTCCATCTACTATTA 1-4-1-6-1-1-4 TgtttCcatctaCtATTA640_10 -21.27 39808 640 TGTTTCCATCTACTATTA 2-1-1-9-2-1-2TGtTtccatctacTAtTA 640_11 -21.24 39808 640 TGTTTCCATCTACTATTA1-3-2-8-1-1-2 TgttTCcatctactAtTA 640_12 -19.51 39808 640TGTTTCCATCTACTATTA 2-1-1-1-1-10-2 TGtTtCcatctactatTA 640_13 -19.94 39808640 TGTTTCCATCTACTATTA 1-1-1-2-1-10-2 TgTttCcatctactatTA 640_14 -19.0839808 641 ACTCTGCAATACACCAA 2-1-1-8-2-1-2 ACtCtgcaatacACcAA 641_1 -19.6144439 641 ACTCTGCAATACACCAA 2-2-1-6-1-1-1-1-2 ACtcTgcaataCaCcAA 641_2-19.77 44439 641 ACTCTGCAATACACCAA 1-2-1-7-1-1-1-1-2 ActCtgcaataCaCcAA641_3 -18.35 44439 641 ACTCTGCAATACACCAA 2-1-2-6-2-2-2 ACtCTgcaataCAccAA641_4 -22.21 44439 641 ACTCTGCAATACACCAA 1-3-1-7-1-1-3 ActcTgcaatacAcCAA641_5 -19.05 44439 641 ACTCTGCAATACACCAA 4-8-1-2-2 ACTCtgcaatacAccAA641_6 -20.30 44439 641 ACTCTGCAATACACCAA 2-1-2-9-3 ACtCTgcaatacacCAA641_7 -21.96 44439 641 ACTCTGCAATACACCAA 2-11-4 ACtctgcaatacaCCAA 641_8-21.68 44439 641 ACTCTGCAATACACCAA 1-1-2-10-3 AcTCtgcaatacacCAA 641_9-20.07 44439 642 CTGTATACACCATCCCA 1-10-1-1-1-1-2 CtgtatacaccAtCcCA642_1 -21.99 46391 642 CTGTATACACCATCCCA 1-10-1-3-2 CtgtatacaccAtccCA642_2 -21.22 46391 642 CTGTATACACCATCCCA 1-1-1-8-1-3-2 CtGtatacaccAtccCA642_3 -21.53 46391 642 CTGTATACACCATCCCA 1-2-1-7-1-3-2 CtgTatacaccAtccCA642_4 -22.31 46391 642 CTGTATACACCATCCCA 1-3-1-6-1-3-2 CtgtAtacaccAtccCA642_5 -21.32 46391 642 CTGTATACACCATCCCA 1-11-2-1-2 CtgtatacaccaTCcCA642_6 -23.06 46391 642 CTGTATACACCATCCCA 1-1-1-1-1-8-1-1-2CtGtAtacaccatCcCA 642_7 -22.35 46391 642 CTGTATACACCATCCCA1-1-1-10-1-1-2 CtGtatacaccatCcCA 642_8 -22.25 46391 642CTGTATACACCATCCCA 1-2-1-9-1-1-2 CtgTatacaccatCcCA 642_9 -23.02 46391 642CTGTATACACCATCCCA 1-3-1-8-1-1-2 CtgtAtacaccatCcCA 642_10 -22.04 46391642 CTGTATACACCATCCCA 1-12-1-1-2 CtgtatacaccatCcCA 642_11 -21.94 46391642 CTGTATACACCATCCCA 2-2-1-10-2 CTgtAtacaccatccCA 642_12 -22.95 46391642 CTGTATACACCATCCCA 1-1-1-1-1-10-2 CtGtAtacaccatccCA 642_13 -21.5846391 642 CTGTATACACCATCCCA 1-1-1-12-2 CtGtatacaccatccCA 642_14 -21.4846391 642 CTGTATACACCATCCCA 1-2-2-10-2 CtgTAtacaccatccCA 642_15 -23.3946391 642 CTGTATACACCATCCCA 1-3-1-10-2 CtgtAtacaccatccCA 642_16 -21.2746391 642 CTGTATACACCATCCCA 1-14-2 CtgtatacaccatccCA 642_17 -21.17 46391642 CTGTATACACCATCCCA 1-3-1-6-3-1-2 CtgtAtacaccATCcCA 642_18 -24.0246391 642 CTGTATACACCATCCCA 1-1-1-8-1-1-1-1-2 CtGtatacaccAtCcCA 642_19-22.30 46391 642 CTGTATACACCATCCCA 1-1-3-6-1-3-2 CtGTAtacaccAtccCA642_20 -24.64 46391 642 CTGTATACACCATCCCA 2-2-1-8-1-1-2CTgtAtacaccatCcCA 642_21 -23.72 46391 642 CTGTATACACCATCCCA 1-3-1-9-3CtgtAtacaccatcCCA 642_22 -23.55 46391 643 TCTGTATACACCATCCCA1-4-1-8-1-1-2 TctgtAtacaccatCcCA 643_1 -22.94 46391 644TCTGTATACACCATCCC 2-10-1-2-2 TCtgtatacaccAtcCC 644_1 -22.70 46392 644TCTGTATACACCATCCC 1-11-1-2-2 TctgtatacaccAtcCC 644_2 -21.11 46392 644TCTGTATACACCATCCC 2-1-1-11-2 TCtGtatacaccatcCC 644_3 -22.96 46392 644TCTGTATACACCATCCC 2-13-2 TCtgtatacaccatcCC 644_4 -22.65 46392 644TCTGTATACACCATCCC 3-9-1-2-2 TCTgtatacaccAtcCC 644_5 -24.39 46392 644TCTGTATACACCATCCC 2-1-1-8-1-2-2 TCtGtatacaccAtcCC 644_6 -23.01 46392 645TTCTGTATACACCATCCC 1-11-1-3-2 TtctgtatacacCatcCC 645_1 -22.57 46392 645TTCTGTATACACCATCCC 1-1-1-10-1-2-2 TtCtgtatacaccAtcCC 645_2 -23.02 46392645 TTCTGTATACACCATCCC 1-3-1-8-1-2-2 TtctGtatacaccAtcCC 645_3 -22.3646392 645 TTCTGTATACACCATCCC 1-12-1-2-2 TtctgtatacaccAtcCC 645_4 -22.0546392 645 TTCTGTATACACCATCCC 1-15-2 TtctgtatacaccatcCC 645_5 -22.0046392 645 TTCTGTATACACCATCCC 1-4-1-6-2-2-2 TtctgTatacacCAtcCC 645_6-25.12 46392 645 TTCTGTATACACCATCCC 1-3-1-8-1-1-3 TtctGtatacaccAtCCC645_7 -24.73 46392 645 TTCTGTATACACCATCCC 3-10-1-2-2 TTCtgtatacaccAtcCC645_8 -24.52 46392 645 TTCTGTATACACCATCCC 1-1-2-9-1-2-2TtCTgtatacaccAtcCC 645_9 -24.71 46392 645 TTCTGTATACACCATCCC1-1-1-1-1-8-1-2-2 TtCtGtatacaccAtcCC 645_10 -23.34 46392 646TTCTGTATACACCATCC 1-10-1-3-2 TtctgtatacaCcatCC 646_1 -19.96 46393 646TTCTGTATACACCATCC 1-12-4 TtctgtatacaccATCC 646_2 -21.16 46393 646TTCTGTATACACCATCC 2-11-1-1-2 TTctgtatacaccAtCC 646_3 -20.11 46393 646TTCTGTATACACCATCC 1-2-1-9-1-1-2 TtcTgtatacaccAtCC 646_4 -20.24 46393 646TTCTGTATACACCATCC 1-3-1-8-1-1-2 TtctGtatacaccAtCC 646_5 -19.54 46393 646TTCTGTATACACCATCC 1-2-1-8-1-2-2 TtcTgtatacacCatCC 646_6 -20.77 46393 646TTCTGTATACACCATCC 1-12-1-1-2 TtctgtatacaccAtCC 646_7 -19.23 46393 646TTCTGTATACACCATCC 1-3-1-7-1-1-3 TtctGtatacacCaTCC 646_8 -21.19 46393 646TTCTGTATACACCATCC 1-1-1-1-1-10-2 TtCtGtatacaccatCC 646_9 -20.47 46393646 TTCTGTATACACCATCC 1-1-1-12-2 TtCtgtatacaccatCC 646_10 -20.16 46393646 TTCTGTATACACCATCC 1-1-1-11-3 TtCtgtatacaccaTCC 646_11 -21.28 46393646 TTCTGTATACACCATCC 1-3-1-9-3 TtctGtatacaccaTCC 646_12 -20.61 46393646 TTCTGTATACACCATCC 1-13-3 TtctgtatacaccaTCC 646_13 -20.30 46393 646TTCTGTATACACCATCC 3-1-1-10-2 TTCtGtatacaccatCC 646_14 -21.96 46393 646TTCTGTATACACCATCC 3-12-2 TTCtgtatacaccatCC 646_15 -21.65 46393 646TTCTGTATACACCATCC 1-1-2-11-2 TtCTgtatacaccatCC 646_16 -21.84 46393 646TTCTGTATACACCATCC 1-2-1-11-2 TtcTgtatacaccatCC 646_17 -20.19 46393 646TTCTGTATACACCATCC 1-3-1-10-2 TtctGtatacaccatCC 646_18 -19.49 46393 646TTCTGTATACACCATCC 1-14-2 TtctgtatacaccatCC 646_19 -19.18 46393 646TTCTGTATACACCATCC 3-8-1-3-2 TTCtgtatacaCcatCC 646_20 -22.44 46393 646TTCTGTATACACCATCC 1-3-1-6-1-3-2 TtctGtatacaCcatCC 646_21 -20.27 46393646 TTCTGTATACACCATCC 1-3-1-7-2-1-2 TtctGtatacacCAtCC 646_22 -21.5346393 646 TTCTGTATACACCATCC 1-1-1-9-1-2-2 TtCtgtatacacCatCC 646_23-20.74 46393 646 TTCTGTATACACCATCC 1-1-1-10-1-1-2 TtCtgtatacaccAtCC646_24 -20.21 46393 647 AGCTTTTAACCAGAGT 2-10-4 AGcttttaaccaGAGT 647_1-21.73 EX-EX 648 AGCTTTTAACCAGAGTG 2-11-4 AGcttttaaccagAGTG 648_1 -22.27EX-EX 649 AGCTTTTAACCAGAGTGG 1-14-3 AgcttttaaccagagTGG 649_1 -21.63EX-EX 650 AGCTTTTAACCAGAGTGGC 1-16-2 AgcttttaaccagagtgGC 650_1 -23.20EX-EX 651 AGCTTTTAACCAGAGTGGCA 1-17-2 AgcttttaaccagagtggCA 651_1 -24.11EX-EX 652 CAGCTTTTAACCAGAGT 2-12-3 CAgcttttaaccagAGT 652_1 -21.65 EX-EX653 CAGCTTTTAACCAGAGTG 3-13-2 CAGcttttaaccagagTG 653_1 -22.27 EX-EX 654CAGCTTTTAACCAGAGTGG 1-15-3 CagcttttaaccagagTGG 654_1 -22.97 EX-EX 655CAGCTTTTAACCAGAGTGGC 1-17-2 CagcttttaaccagagtgGC 655_1 -24.53 EX-EX 656CTTTTAACCAGAGTG 4-7-4 CTTTtaaccagAGTG 656_1 -20.12 EX-EX 657CTTTTAACCAGAGTGG 4-9-3 CTTTtaaccagagTGG 657_1 -20.92 EX-EX 658CTTTTAACCAGAGTGGC 4-11-2 CTTTtaaccagagtgGC 658_1 -22.48 EX-EX 659CTTTTAACCAGAGTGGCA 1-14-3 CttttaaccagagtgGCA 659_1 -22.96 EX-EX 660CTTTTAACCAGAGTGGCAT 3-13-3 CTTttaaccagagtggCAT 660_1 -24.65 EX-EX 661CTTTTAACCAGAGTGGCATC 2-16-2 CTtttaaccagagtggcaTC 661_1 -23.19 EX-EX 662GCTTTTAACCAGAGT 3-9-3 GCTtttaaccagAGT 662_1 -21.02 EX-EX 663GCTTTTAACCAGAGTG 4-10-2 GCTTttaaccagagTG 663_1 -21.02 EX-EX 664GCTTTTAACCAGAGTGG 1-12-4 GcttttaaccagaGTGG 664_1 -22.24 EX-EX 665GCTTTTAACCAGAGTGGC 1-14-3 GcttttaaccagagtGGC 665_1 -23.42 EX-EX 666GCTTTTAACCAGAGTGGCA 1-16-2 GcttttaaccagagtggCA 666_1 -22.94 EX-EX 667GCTTTTAACCAGAGTGGCAT 1-16-3 GcttttaaccagagtggCAT 667_1 -25.01 EX-EX 668TCAGCTTTTAACCAGAGT 2-13-3 TCagcttttaaccagAGT 668_1 -22.18 EX-EX 669TCAGCTTTTAACCAGAGTG 2-14-3 TCagcttttaaccagaGTG 669_1 -23.15 EX-EX 670TCAGCTTTTAACCAGAGTGG 2-16-2 TCagcttttaaccagagtGG 670_1 -23.41 EX-EX 671TTCAGCTTTTAACCAGAGT 2-14-3 TTcagcttttaaccagAGT 671_1 -22.72 EX-EX 672TTCAGCTTTTAACCAGAGTG 2-15-3 TTcagcttttaaccagaGTG 672_1 -23.69 EX-EX 673TTTCAGCTTTTAACCAGAGT 2-15-3 TTtcagcttttaaccagAGT 673_1 -23.66 EX-EX 674TTTTAACCAGAGTGGC 1-11-4 TtttaaccagagTGGC 674_1 -20.81 EX-EX 675TTTTAACCAGAGTGGCA 3-11-3 TTTtaaccagagtgGCA 675_1 -22.30 EX-EX 676TTTTAACCAGAGTGGCAT 4-11-3 TTTTaaccagagtggCAT 676_1 -23.21 EX-EX 677TTTTAACCAGAGTGGCATC 4-13-2 TTTTaaccagagtggcaTC 677_1 -22.57 EX-EX 678TTTTAACCAGAGTGGCATCC 2-16-2 TTttaaccagagtggcatCC 678_1 -24.58 EX-EX 679ATCAATATCTTCTCACT 1-1-2-7-1-1-1-1-2 AtCAatatcttCtCaCT 679_1 -19.16 5782679 ATCAATATCTTCTCACT 5-6-1-2-3 ATCAAtatcttCtcACT 679_2 -21.49 5782 679ATCAATATCTTCTCACT 1-1-1-1-1-7-5 AtCaAtatcttcTCACT 679_3 -20.18 5782 679ATCAATATCTTCTCACT 1-1-3-8-4 AtCAAtatcttctCACT 679_4 -20.66 5782 679ATCAATATCTTCTCACT 3-10-1-1-2 ATCaatatcttctCaCT 679_5 -18.62 5782 680TATCAATATCTTCTCACT 2-2-1-7-1-1-1-1-2 TAtcAatatcttCtCaCT 680_1 -19.315782 680 TATCAATATCTTCTCACT 1-1-2-8-1-1-1-1-2 TaTCaatatcttCtCaCT 680_2-19.89 5782 680 TATCAATATCTTCTCACT 1-2-3-6-1-2-3 TatCAAtatcttCtcACT680_3 -20.66 5782 680 TATCAATATCTTCTCACT 1-2-3-7-2-1-2TatCAAtatcttcTCaCT 680_4 -20.99 5782 680 TATCAATATCTTCTCACT 2-1-1-10-4TAtCaatatcttctCACT 680_5 -20.89 5782 681 TATCAATATCTTCTCAC 4-7-2-1-3TATCaatatctTCtCAC 681_1 -21.30 5783 681 TATCAATATCTTCTCAC 1-2-2-6-2-1-3TatCAatatctTCtCAC 681_2 -19.73 5783 681 TATCAATATCTTCTCAC 2-1-1-8-5TAtCaatatcttCTCAC 681_3 -20.26 5783 681 TATCAATATCTTCTCAC 1-1-3-7-5TaTCAatatcttCTCAC 681_4 -21.74 5783 681 TATCAATATCTTCTCAC 5-9-3TATCAatatcttctCAC 681_5 -20.83 5783 682 TTATCAATATCTTCTCAC1-1-1-1-2-6-2-2-2 TtAtCAatatctTCtcAC 682_1 -18.32 5783 682TTATCAATATCTTCTCAC 1-3-1-8-5 TtatCaatatcttCTCAC 682_2 -19.71 5783 682TTATCAATATCTTCTCAC 3-10-1-1-3 TTAtcaatatcttCtCAC 682_3 -19.53 5783 682TTATCAATATCTTCTCAC 2-1-2-8-1-1-3 TTaTCaatatcttCtCAC 682_4 -20.20 5783682 TTATCAATATCTTCTCAC 1-2-3-9-3 TtaTCAatatcttctCAC 682_5 -19.47 5783683 TTATCAATATCTTCTCACT 1-1-1-1-1-8-1-1-1-1-2 TtAtCaatatcttCtCaCT 683_1-19.45 5782 683 TTATCAATATCTTCTCACT 1-3-1-8-1-1-1-1-2TtatCaatatcttCtCaCT 683_2 -19.35 5782 683 TTATCAATATCTTCTCACT1-1-1-1-1-8-1-2-3 TtAtCaatatcttCtcACT 683_3 -19.33 5782 683TTATCAATATCTTCTCACT 1-1-1-2-1-7-1-3-2 TtAtcAatatcttCtcaCT 683_4 -18.185782 683 TTATCAATATCTTCTCACT 1-1-1-2-1-9-4 TtAtcAatatcttctCACT 683_5-19.84 5782 684 ACCTTTCTTTAACCCTTT 2-1-1-8-2-1-3 ACcTttctttaaCCcTTT684_1 -25.24 8113 684 ACCTTTCTTTAACCCTTT 2-10-1-1-1-1-2ACctttctttaaCcCtTT 684_2 -22.31 8113 684 ACCTTTCTTTAACCCTTT1-1-1-9-1-1-1-1-2 AcCtttctttaaCcCtTT 684_3 -22.01 8113 684ACCTTTCTTTAACCCTTT 1-1-1-1-1-9-1-1-2 AcCtTtctttaaccCtTT 684_4 -21.538113 684 ACCTTTCTTTAACCCTTT 1-1-1-11-1-1-2 AcCtttctttaaccCtTT 684_5-21.23 8113 685 TACCTTTCTTTAACCCTTT 1-2-1-8-1-1-1-2-2TacCtttctttaAcCctTT 685_1 -22.44 8113 685 TACCTTTCTTTAACCCTTT1-2-1-1-1-7-1-1-1-1-2 TacCtTtctttaaCcCtTT 685_2 -23.32 8113 685TACCTTTCTTTAACCCTTT 2-1-1-10-1-1-3 TAcCtttctttaacCcTTT 685_3 -24.28 8113685 TACCTTTCTTTAACCCTTT 1-1-1-12-1-1-2 TaCctttctttaaccCtTT 685_4 -22.138113 685 TACCTTTCTTTAACCCTTT 1-2-1-11-1-1-2 TacCtttctttaaccCtTT 685_5-22.23 8113 686 ATACCTTTCTTTAACCC 1-2-1-7-1-1-1-1-2 AtaCctttcttTaAcCC686_1 -20.53 8116 686 ATACCTTTCTTTAACCC 1-3-1-6-1-3-2 AtacCtttcttTaacCC686_2 -20.21 8116 686 ATACCTTTCTTTAACCC 2-2-1-7-2-1-2 ATacCtttctttAAcCC686_3 -21.89 8116 686 ATACCTTTCTTTAACCC 1-1-1-1-1-8-1-1-2AtAcCtttctttaAcCC 686_4 -20.10 8116 686 ATACCTTTCTTTAACCC 1-2-1-10-3AtaCctttctttaaCCC 686_5 -21.76 8116 687 ATACCTTTCTTTAACCCTT1-3-2-6-1-2-4 AtacCTttctttAacCCTT 687_1 -26.10 8114 687ATACCTTTCTTTAACCCTT 1-1-1-1-1-8-1-1-1-1-2 AtAcCtttctttaAcCcTT 687_2-22.23 8114 687 ATACCTTTCTTTAACCCTT 1-2-1-9-1-1-1-1-2AtaCctttctttaAcCcTT 687_3 -21.93 8114 687 ATACCTTTCTTTAACCCTT1-2-1-1-1-8-2-1-2 AtaCcTttctttaaCCcTT 687_4 -24.41 8114 687ATACCTTTCTTTAACCCTT 1-3-1-11-3 AtacCtttctttaaccCTT 687_5 -22.51 8114 688ATACCTTTCTTTAACCCTTT 1-3-1-8-1-1-1-2-2 AtacCtttctttaAcCctTT 688_1 -22.838113 688 ATACCTTTCTTTAACCCTTT 1-3-1-9-1-1-1-1-2 AtacCtttctttaaCcCtTT688_2 -23.41 8113 688 ATACCTTTCTTTAACCCTTT 1-4-2-7-1-2-3AtaccTTtctttaaCccTTT 688_3 -23.98 8113 688 ATACCTTTCTTTAACCCTTT1-1-1-1-1-10-1-1-3 AtAcCtttctttaacCcTTT 688_4 -23.63 8113 688ATACCTTTCTTTAACCCTTT 1-2-1-12-1-1-2 AtaCctttctttaaccCtTT 688_5 -22.528113 689 ATACCTTTCTTTAACCCT 1-3-2-6-2-2-2 AtacCTttctttAAccCT 689_1-22.61 8115 689 ATACCTTTCTTTAACCCT 1-1-1-1-2-8-1-1-2 AtAcCTttctttaaCcCT689_2 -22.85 8115 689 ATACCTTTCTTTAACCCT 1-2-1-10-1-1-2AtaCctttctttaaCcCT 689_3 -21.36 8115 689 ATACCTTTCTTTAACCCT 1-2-3-10-2AtaCCTttctttaaccCT 689_4 -24.26 8115 689 ATACCTTTCTTTAACCCT 1-3-1-11-2AtacCtttctttaaccCT 689_5 -20.69 8115 690 TATACCTTTCTTTAACCCT2-2-1-10-1-1-2 TAtaCctttctttaaCcCT 690_1 -23.60 8115 690TATACCTTTCTTTAACCCT 1-4-1-9-1-1-2 TatacCtttctttaaCcCT 690_2 -22.57 8115690 TATACCTTTCTTTAACCCT 2-3-1-11-2 TAtacCtttctttaaccCT 690_3 -22.92 8115690 TATACCTTTCTTTAACCCT 1-3-1-12-2 TataCctttctttaaccCT 690_4 -21.68 8115690 TATACCTTTCTTTAACCCT 1-4-1-11-2 TatacCtttctttaaccCT 690_5 -21.79 8115691 TTATACCTTTCTTTAAC 4-7-2-2-2 TTATacctttcTTtaAC 691_1 -18.49 8118 691TTATACCTTTCTTTAAC 3-8-1-1-4 TTAtacctttcTtTAAC 691_2 -18.07 8118 692TTATACCTTTCTTTAACCC 2-10-1-1-1-2-2 TTatacctttctTtAacCC 692_1 -21.94 8116692 TTATACCTTTCTTTAACCC 1-1-1-9-1-4-2 TtAtacctttctTtaacCC 692_2 -20.688116 692 TTATACCTTTCTTTAACCC 1-4-1-7-1-3-2 TtataCctttcttTaacCC 692_3-21.79 8116 692 TTATACCTTTCTTTAACCC 1-3-2-8-2-1-2 TtatACctttctttAAcCC692_4 -22.39 8116 692 TTATACCTTTCTTTAACCC 1-1-1-2-1-9-1-1-2TtAtaCctttctttaAcCC 692_5 -21.58 8116 693 TTATACCTTTCTTTAACC2-3-1-6-1-3-2 TTataCctttctTtaaCC 693_1 -19.80 8117 693TTATACCTTTCTTTAACC 1-1-1-1-2-6-1-3-2 TtAtACctttctTtaaCC 693_2 -19.258117 693 TTATACCTTTCTTTAACC 1-3-2-7-2-1-2 TtatACctttcttTAaCC 693_3-20.74 8117 693 TTATACCTTTCTTTAACC 1-1-1-2-1-7-1-2-2 TtAtaCctttcttTaaCC693_4 -19.08 8117 693 TTATACCTTTCTTTAACC 1-2-1-1-1-8-4TtaTaCctttctttAACC 693_5 -20.26 8117 694 TTTATACCTTTCTTTAACC2-1-1-8-2-3-2 TTTAtacctttcTTtaaCC 694_1 -20.72 8117 694TTTATACCTTTCTTTAACC 1-4-1-6-1-2-4 TttatAcctttcTttAACC 694_2 -20.33 8117694 TTTATACCTTTCTTTAACC 2-11-1-1-1-1-2 TTtatacctttctTtAaCC 694_3 -19.728117 694 TTTATACCTTTCTTTAACC 1-1-2-9-1-3-2 TtTAtacctttctTtaaCC 694_4-20.65 8117 694 TTTATACCTTTCTTTAACC 1-3-2-7-1-3-2 TttaTAcctttctTtaaCC694_5 -20.88 8117 695 TTTATACCTTTCTTTAAC 3-9-3-1-2 TTTatacctttcTTTaAC695_1 -18.74 8118 695 TTTATACCTTTCTTTAAC 5-7-2-2-2 TTTATacctttcTTtaAC695_2 -20.31 8118 695 TTTATACCTTTCTTTAAC 1-1-3-7-2-2-2TtTATacctttcTTtaAC 695_3 -18.98 8118 695 TTTATACCTTTCTTTAAC 4-8-1-1-4TTTAtacctttcTtTAAC 695_4 -19.89 8118 695 TTTATACCTTTCTTTAAC 2-3-1-7-5TTtatAcctttctTTAAC 695_5 -18.02 8118 696 TTTTATACCTTTCTTTAAC2-3-1-6-3-2-2 TTttaTacctttCTTtaAC 696_1 -19.79 8118 696TTTTATACCTTTCTTTAAC 1-1-2-8-2-1-1-1-2 TtTTatacctttCTtTaAC 696_2 -19.578118 696 TTTTATACCTTTCTTTAAC 2-1-2-7-2-2-3 TTtTAtacctttCTttAAC 696_3-20.28 8118 696 TTTTATACCTTTCTTTAAC 3-9-1-1-5 TTTtatacctttCtTTAAC 696_4-20.62 8118 696 TTTTATACCTTTCTTTAAC 1-1-3-7-1-1-1-2-2TtTTAtacctttCtTtaAC 696_5 -19.08 8118 697 TGTACTTTCCTTTACCA 2-9-1-3-2TGtactttcctTtacCA 697_1 -20.68 11462 697 TGTACTTTCCTTTACCA 1-2-1-7-1-3-2TgtActttcctTtacCA 697_2 -19.66 11462 697 TGTACTTTCCTTTACCA 1-3-1-6-1-3-2TgtaCtttcctTtacCA 697_3 -20.46 11462 697 TGTACTTTCCTTTACCA 2-2-1-8-1-1-2TGtaCtttcctttAcCA 697_4 -21.56 11462 697 TGTACTTTCCTTTACCA 1-3-1-9-3TgtaCtttcctttaCCA 697_5 -22.54 11462 698 TTATACACCATCATTAT 4-7-3-1-2TTATacaccatCATTAT 698_1 -21.13 11506 698 TTATACACCATCATTAT 4-7-2-1-3TTATacaccatCAtTAT 698_2 -21.64 11506 698 TTATACACCATCATTAT 3-8-1-1-4TTAtacaccatCaTTAT 698_3 -19.45 11506 698 TTATACACCATCATTAT 2-1-2-7-5TTaTAcaccatcATTAT 698_4 -20.61 11506 698 TTATACACCATCATTAT 5-9-3TTATAcaccatcatTAT 698_5 -20.74 11506 699 TTATACACCATCATTATA3-2-1-6-2-2-2 TTAtaCaccatcATtaTA 699_1 -19.38 11505 699TTATACACCATCATTATA 1-2-3-6-1-1-4 TtaTACaccatcAtTATA 699_2 -20.93 11505699 TTATACACCATCATTATA 4-1-1-7-2-1-2 TTATaCaccatcaTTaTA 699_3 -21.4411505 699 TTATACACCATCATTATA 2-1-2-8-1-1-3 TTaTAcaccatcaTtATA 699_4-19.71 11505 699 TTATACACCATCATTATA 3-2-1-8-4 TTAtaCaccatcatTATA 699_5-20.75 11505 700 TTTATACACCATCATTAT 2-1-2-7-3-1-2 TTtATacaccatCATtAT700_1 -20.67 11506 700 TTTATACACCATCATTAT 3-1-1-7-2-1-3TTTaTacaccatCAtTAT 700_2 -21.52 11506 700 TTTATACACCATCATTAT1-3-2-6-2-1-3 TttaTAcaccatCAtTAT 700_3 -20.70 11506 700TTTATACACCATCATTAT 1-1-3-8-1-1-3 TtTATacaccatcAtTAT 700_4 -20.05 11506700 TTTATACACCATCATTAT 3-1-1-9-4 TTTaTacaccatcaTTAT 700_5 -20.34 11506701 TTTATACACCATCATTATA 4-8-1-1-2-1-2 TTTAtacaccatCaTTaTA 701_1 -21.5711505 701 TTTATACACCATCATTATA 2-2-1-7-1-2-4 TTtaTacaccatCatTATA 701_2-21.05 11505 701 TTTATACACCATCATTATA 1-1-1-1-1-8-2-1-3TtTaTacaccatcATtATA 701_3 -19.83 11505 701 TTTATACACCATCATTATA2-2-2-7-2-2-2 TTtaTAcaccatcATtaTA 701_4 -20.24 11505 701TTTATACACCATCATTATA 1-1-3-10-1-1-2 TtTATacaccatcatTaTA 701_5 -20.3011505 702 ATTTATACACCATCATTAT 1-1-1-2-1-7-3-1-2 AtTtaTacaccatCATtAT702_1 -20.07 11506 702 ATTTATACACCATCATTAT 1-1-2-1-1-7-2-2-2AtTTaTacaccatCAttAT 702_2 -20.07 11506 702 ATTTATACACCATCATTAT2-1-2-8-1-1-1-1-2 ATtTAtacaccatCaTtAT 702_3 -19.74 11506 702ATTTATACACCATCATTAT 2-3-1-7-1-2-3 ATttaTacaccatCatTAT 702_4 -20.07 11506702 ATTTATACACCATCATTAT 1-1-1-1-1-10-4 AtTtAtacaccatcaTTAT 702_5 -18.6411506 703 ATTTATACACCATCATTATA 1-4-1-7-1-2-4 AtttaTacaccatCatTATA 703_1-21.05 11505 703 ATTTATACACCATCATTATA 2-1-1-2-1-7-2-2-2ATtTatAcaccatcATtaTA 703_2 -20.32 11505 703 ATTTATACACCATCATTATA1-1-1-2-1-8-1-1-1-1-2 AtTtaTacaccatcAtTaTA 703_3 -18.80 11505 703ATTTATACACCATCATTATA 1-2-3-8-1-1-1-1-2 AttTATacaccatcAtTaTA 703_4 -21.1711505 703 ATTTATACACCATCATTATA 3-1-1-9-1-2-3 ATTTAtacaccatcAttATA 703_5-19.97 11505 704 TATTTATACACCATCATTA 1-2-3-6-2-3-2 TatTTAtacaccATcatTA704_1 -20.37 11507 704 TATTTATACACCATCATTA 4-8-1-1-2-1-2TATTtatacaccAtCAtTA 704_2 -21.70 11507 704 TATTTATACACCATCATTA1-1-1-1-1-7-1-1-1-1-3 TaTtTatacaccAtCaTTA 704_3 -19.16 11507 704TATTTATACACCATCATTA 2-2-1-8-2-2-2 TAttTatacaccaTCatTA 704_4 -19.98 11507704 TATTTATACACCATCATTA 2-2-1-10-4 TAttTatacaccatcATTA 704_5 -19.9911507 705 TATTTATACACCATCATTAT 2-2-1-1-1-7-2-2-2 TAttTaTacaccatCAttAT705_1 -21.49 11506 705 TATTTATACACCATCATTAT 2-1-1-10-1-1-4TAtTtatacaccatCaTTAT 705_2 -21.44 11506 705 TATTTATACACCATCATTAT1-1-1-2-1-8-1-1-1-1-2 TaTttAtacaccatCaTtAT 705_3 -18.27 11506 705TATTTATACACCATCATTAT 2-1-2-9-1-3-2 TAtTTatacaccatCattAT 705_4 -19.9711506 705 TATTTATACACCATCATTAT 1-2-3-9-1-1-3 TatTTAtacaccatcAtTAT 705_5-21.11 11506 706 TTATTTATACACCATCATTA 2-3-1-7-1-1-1-1-3TTattTatacaccAtCaTTA 706_1 -20.54 11507 706 TTATTTATACACCATCATTA1-1-2-1-1-7-1-2-4 TtATtTatacaccAtcATTA 706_2 -20.84 11507 706TTATTTATACACCATCATTA 1-1-1-2-1-8-2-2-2 TtAttTatacaccaTCatTA 706_3 -19.5211507 706 TTATTTATACACCATCATTA 1-2-3-8-1-1-1-1-2 TtaTTTatacaccaTcAtTA706_4 -19.96 11507 706 TTATTTATACACCATCATTA 3-1-1-11-1-1-2TTAtTtatacaccatcAtTA 706_5 -19.63 11507 707 ATTATTTATACACCATCAT2-2-2-6-3-2-2 ATtaTTtatacaCCAtcAT 707_1 -22.41 11509 707ATTATTTATACACCATCAT 2-3-1-6-1-2-4 ATtatTtatacaCcaTCAT 707_2 -21.02 11509707 ATTATTTATACACCATCAT 1-1-1-1-1-8-3-1-2 AtTaTttatacacCATcAT 707_3-20.01 11509 707 ATTATTTATACACCATCAT 1-1-2-1-1-7-1-2-3AtTAtTtatacacCatCAT 707_4 -20.30 11509 707 ATTATTTATACACCATCAT2-1-2-9-1-1-3 ATtATttatacaccAtCAT 707_5 -20.20 11509 708ATTATTTATACACCATCA 2-2-2-6-2-2-2 ATtaTTtatacaCCatCA 708_1 -20.96 11510708 ATTATTTATACACCATCA 3-1-1-7-1-1-4 ATTaTttatacaCcATCA 708_2 -21.1911510 708 ATTATTTATACACCATCA 1-1-3-7-1-3-2 AtTATttatacaCcatCA 708_3-19.39 11510 708 ATTATTTATACACCATCA 1-1-1-2-1-7-2-1-2 AtTatTtatacacCAtCA708_4 -18.57 11510 708 ATTATTTATACACCATCA 2-1-2-8-1-1-3ATTATttatacacCaTCA 708_5 -19.79 11510 709 ATTATTTATACACCATCATT1-2-3-7-1-1-2-1-2 AttATTtatacacCaTCaTT 709_1 -20.97 11508 709ATTATTTATACACCATCATT 1-1-1-2-2-6-1-4-2 AtTatTTatacacCatcaTT 709_2 -19.2911508 709 ATTATTTATACACCATCATT 1-1-1-2-1-8-2-1-3 AtTatTtatacaccATcATT709_3 -19.70 11508 709 ATTATTTATACACCATCATT 3-1-1-9-1-1-1-1-2ATTaTttatacaccAtCaTT 709_4 -20.09 11508 709 ATTATTTATACACCATCATT2-1-2-1-1-7-1-2-3 ATtATtTatacaccAtcATT 709_5 -20.67 11508 710ATTATTTATACACCATC 5-6-3-1-2 ATTATttatacACCaTC 710_1 -21.70 11511 710ATTATTTATACACCATC 5-6-2-1-3 ATTATttatacACcATC 710_2 -20.38 11511 710ATTATTTATACACCATC 2-2-1-7-5 ATtaTttatacaCCATC 710_3 -20.25 11511 710ATTATTTATACACCATC 1-1-2-8-5 AtTAtttatacaCCATC 710_4 -20.42 11511 710ATTATTTATACACCATC 5-8-4 ATTATttatacacCATC 710_5 -21.04 11511 711AATTATTTATACACCATC 2-2-2-6-3-1-2 AAttATttatacACCaTC 711_1 -18.93 11511711 AATTATTTATACACCATC 2-1-3-6-1-1-4 AAtTATttatacAcCATC 711_2 -20.1811511 711 AATTATTTATACACCATC 4-1-1-7-5 AATTaTttatacaCCATC 711_3 -22.2411511 711 AATTATTTATACACCATC 2-1-2-8-5 AAtTAtttatacaCCATC 711_4 -21.1711511 711 AATTATTTATACACCATC 1-1-4-7-2-1-2 AaTTATttatacaCCaTC 711_5-20.58 11511 712 AATTATTTATACACCATCA 1-2-1-1-1-6-3-2-2AatTaTttatacACCatCA 712_1 -20.42 11510 712 AATTATTTATACACCATCA2-2-1-7-1-1-2-1-2 AAttAtttatacAcCAtCA 712_2 -18.54 11510 712AATTATTTATACACCATCA 1-1-3-7-1-2-4 AaTTAtttatacAccATCA 712_3 -20.67 11510712 AATTATTTATACACCATCA 2-1-2-8-2-1-3 AAtTAtttatacaCCaTCA 712_4 -22.2011510 712 AATTATTTATACACCATCA 3-1-1-8-1-2-3 AATtAtttatacaCcaTCA 712_5-19.50 11510 713 AAATTATTTATACACCATC 3-2-1-6-3-1-3 AAAttAtttataCACcATC713_1 -19.21 11511 713 AAATTATTTATACACCATC 1-2-3-6-3-2-2AaaTTAtttataCACcaTC 713_2 -20.01 11511 713 AAATTATTTATACACCATC1-1-3-7-2-1-4 AaATTatttataCAcCATC 713_3 -21.68 11511 713AAATTATTTATACACCATC 2-1-2-7-1-1-2-1-2 AAaTTatttataCaCCaTC 713_4 -19.6311511 713 AAATTATTTATACACCATC 1-1-2-1-1-8-5 AaATtAtttatacaCCATC 713_5-20.67 11511 714 AAATTATTTATACACCAT 1-1-4-6-2-1-3 AaATTAtttataCAcCAT714_1 -20.31 11512 714 AAATTATTTATACACCAT 2-2-2-6-1-1-4AAatTAtttataCaCCAT 714_2 -19.59 11512 714 AAATTATTTATACACCAT1-1-3-7-1-1-4 AaATTatttataCaCCAT 714_3 -20.00 11512 714AAATTATTTATACACCAT 4-9-5 AAATtatttatacACCAT 714_4 -19.36 11512 714AAATTATTTATACACCAT 3-1-2-7-5 AAAtTAtttatacACCAT 714_5 -19.98 11512 715AAAATTATTTATACACCAT 2-1-2-7-3-1-3 AAaATtatttatACAcCAT 715_1 -19.29 11512715 AAAATTATTTATACACCAT 1-3-2-6-2-1-4 AaaaTTatttatACaCCAT 715_2 -19.6811512 715 AAAATTATTTATACACCAT 3-2-1-6-1-1-5 AAAatTatttatAcACCAT 715_3-19.27 11512 715 AAAATTATTTATACACCAT 1-1-4-7-1-1-4 AaAATTatttataCaCCAT715_4 -20.75 11512 715 AAAATTATTTATACACCAT 2-1-2-9-5 AAaATtatttatacACCAT715_5 -19.38 11512 716 TAAAATTATTTATACACC 2-1-3-6-3-1-2TAaAATtatttaTACaCC 716_1 -18.88 11514 716 TAAAATTATTTATACACC 3-1-2-7-5TAAaATtatttatACACC 716_2 -18.95 11514 716 TAAAATTATTTATACACC 1-1-4-7-5TaAAATtatttatACACC 716_3 -18.33 11514 716 TAAAATTATTTATACACC 3-1-2-8-4TAAaATtatttataCACC 716_4 -18.35 11514 716 TAAAATTATTTATACACC 2-1-3-8-4TAaAATtatttataCACC 716_5 -18.35 11514 717 GTAAAATTATTTATACACC2-1-3-6-4-1-2 GTaAAAttatttATACaCC 717_1 -21.68 11514 717GTAAAATTATTTATACACC 3-2-1-6-2-2-3 GTAaaAttatttATacACC 717_2 -20.00 11514717 GTAAAATTATTTATACACC 3-1-2-7-2-1-3 GTAaAAttatttaTAcACC 717_3 -20.8611514 717 GTAAAATTATTTATACACC 2-1-3-7-1-1-4 GTaAAAttatttaTaCACC 717_4-21.11 11514 717 GTAAAATTATTTATACACC 4-1-1-8-5 GTAAaAttatttatACACC 717_5-21.46 11514 718 GTAAAATTATTTATACAC 4-1-1-7-5 GTAAaAttatttaTACAC 718_1-18.17 11515 718 GTAAAATTATTTATACAC 3-1-2-7-5 GTAaAAttatttaTACAC 718_2-18.17 11515 719 GAGTATATTACCTCCA 3-10-3 GAGtatattacctCCA 719_1 -22.5615162 719 GAGTATATTACCTCCA 2-1-1-9-3 GAgTatattacctCCA 719_2 -22.24 15162719 GAGTATATTACCTCCA 2-11-3 GAgtatattacctCCA 719_3 -21.15 15162 719GAGTATATTACCTCCA 1-1-3-8-3 GaGTAtattacctCCA 719_4 -22.93 15162 719GAGTATATTACCTCCA 5-9-2 GAGTAtattacctcCA 719_5 -23.29 15162 720CTTTTCTATAATCTCAC 2-2-1-6-3-1-2 CTttTctataaTCTcAC 720_1 -18.54 30553 720CTTTTCTATAATCTCAC 3-8-2-1-3 CTTttctataaTCtCAC 720_2 -19.80 30553 720CTTTTCTATAATCTCAC 1-1-3-6-1-1-4 CtTTTctataaTcTCAC 720_3 -19.40 30553 720CTTTTCTATAATCTCAC 4-8-5 CTTTtctataatCTCAC 720_4 -21.37 30553 720CTTTTCTATAATCTCAC 1-3-1-7-5 CtttTctataatCTCAC 720_5 -18.92 30553 721CTTTTCTATAATCTCACA 2-3-1-6-1-1-1-1-2 CTtttCtataatCtCaCA 721_1 -20.1730552 721 CTTTTCTATAATCTCACA 1-1-1-1-2-6-1-2-3 CtTtTCtataatCtcACA 721_2-20.15 30552 721 CTTTTCTATAATCTCACA 1-2-1-1-1-7-2-1-2 CttTtCtataatcTCaCA721_3 -19.50 30552 721 CTTTTCTATAATCTCACA 1-1-3-8-1-1-3CtTTTctataatcTcACA 721_4 -19.49 30552 721 CTTTTCTATAATCTCACA 3-2-1-8-4CTTttCtataatctCACA 721_5 -21.97 30552 722 TCTTTTCTATAATCTCACA1-1-3-7-1-1-1-1-3 TcTTTtctataaTcTcACA 722_1 -21.04 30552 722TCTTTTCTATAATCTCACA 1-4-1-6-1-2-1-1-2 TctttTctataaTctCaCA 722_2 -18.8130552 722 TCTTTTCTATAATCTCACA 2-2-1-8-1-2-3 TCttTtctataatCtcACA 722_3-20.68 30552 722 TCTTTTCTATAATCTCACA 2-1-1-9-1-3-2 TCtTttctataatCtcaCA722_4 -20.13 30552 722 TCTTTTCTATAATCTCACA 2-13-1-1-2TCttttctataatctCaCA 722_5 -19.52 30552 723 TCTTTTCTATAATCTCAC2-1-1-8-2-2-2 TCtTttctataaTCtcAC 723_1 -18.51 30553 723TCTTTTCTATAATCTCAC 3-10-1-1-3 TCTtttctataatCtCAC 723_2 -20.36 30553 723TCTTTTCTATAATCTCAC 1-2-3-7-1-1-3 TctTTTctataatCtCAC 723_3 -19.57 30553723 TCTTTTCTATAATCTCAC 2-2-2-8-4 TCttTTctataatcTCAC 723_4 -20.57 30553723 TCTTTTCTATAATCTCAC 1-1-4-8-4 TcTTTTctataatcTCAC 723_5 -20.82 30553724 ATCTTTTCTATAATCTCACA 1-1-1-1-1-9-1-1-1-1-2 AtCtTttctataatCtCaCA724_1 -20.93 30552 724 ATCTTTTCTATAATCTCACA 1-1-1-11-1-2-3AtCttttctataatCtcACA 724_2 -20.51 30552 724 ATCTTTTCTATAATCTCACA1-2-1-1-1-8-1-2-3 AtcttTtctataatCtcACA 724_3 -20.35 30552 724ATCTTTTCTATAATCTCACA 1-3-2-8-1-3-2 AtctTTtctataatCtcaCA 724_4 -20.1030552 724 ATCTTTTCTATAATCTCACA 1-1-1-2-1-10-1-1-2 AtCttTtctataatctCaCA724_5 -19.95 30552 725 ATCTTTTCTATAATCTCAC 1-1-1-9-1-1-1-1-3AtCttttctataAtCtCAC 725_1 -19.62 30553 725 ATCTTTTCTATAATCTCAC1-2-2-7-1-1-1-1-3 AtcttttctataAtCtCAC 725_2 -19.97 30553 725ATCTTTTCTATAATCTCAC 1-1-2-1-1-7-2-2-2 AtCTtTtctataaTCtcAC 725_3 -19.8330553 725 ATCTTTTCTATAATCTCAC 1-2-1-1-1-9-4 AtcttTtctataatcTCAC 725_4-19.36 30553 725 ATCTTTTCTATAATCTCAC 3-13-3 ATCttttctataatctCAC 725_5-20.25 30553 726 ATCTTTTCTATAATCTCA 1-1-2-8-1-1-1-1-2 AtCTtttctataAtCtCA726_1 -18.77 30554 726 ATCTTTTCTATAATCTCA 3-1-1-7-1-2-3ATCtTttctataAtcTCA 726_2 -20.03 30554 726 ATCTTTTCTATAATCTCA 3-10-2-1-2ATCttttctataaTCtCA 726_3 -20.31 30554 726 ATCTTTTCTATAATCTCA1-1-1-1-2-7-2-1-2 AtCtTTtctataaTCtCA 726_4 -19.49 30554 726ATCTTTTCTATAATCTCA 1-1-3-9-4 AtCTTttctataatCTCA 726_5 -21.14 30554 727CATCTTTTCTATAATCTCAC 2-11-1-1-1-2-2 CAtcttttctataAtCtcAC 727_1 -19.8630553 727 CATCTTTTCTATAATCTCAC 1-1-2-9-1-1-1-2-2 CaTCttttctataAtCtcAC727_2 -20.49 30553 727 CATCTTTTCTATAATCTCAC 1-3-1-1-1-8-1-1-3CatcTtTtctataatCtCAC 727_3 -20.97 30553 727 CATCTTTTCTATAATCTCAC1-2-1-1-1-9-1-2-2 CatCtTttctataatCtcAC 727_4 -19.35 30553 727CATCTTTTCTATAATCTCAC 2-1-1-2-1-10-3 CAtCttTtctataatctCAC 727_5 -21.9230553 728 CATCTTTTCTATAATCTCA 1-3-1-7-2-1-1-1-2 CatcTtttctatAAtCtCA728_1 -19.26 30554 728 CATCTTTTCTATAATCTCA 2-3-1-6-2-2-3CAtctTttctatAAtcTCA 728_2 -20.74 30554 728 CATCTTTTCTATAATCTCA1-2-1-8-1-2-1-1-2 CatCttttctatAatCtCA 728_3 -19.21 30554 728CATCTTTTCTATAATCTCA 2-1-1-1-1-9-1-1-2 CAtCtTttctataatCtCA 728_4 -20.8630554 728 CATCTTTTCTATAATCTCA 1-1-2-13-2 CaTCttttctataatctCA 728_5-19.23 30554 729 TCATCTTTTCTATAATCTCA 1-1-1-2-1-7-2-1-1-1-2TcAtcTtttctatAAtCtCA 729_1 -20.53 30554 729 TCATCTTTTCTATAATCTCA2-4-1-6-2-3-2 TCatctTttctatAAtctCA 729_2 -20.57 30554 729TCATCTTTTCTATAATCTCA 2-2-1-8-1-2-1-1-2 TCatCttttctatAatCtCA 729_3 -21.7030554 729 TCATCTTTTCTATAATCTCA 3-13-1-1-2 TCAtcttttctataatCtCA 729_4-22.07 30554 729 TCATCTTTTCTATAATCTCA 3-1-1-13-2 TCAtCttttctataatctCA729_5 -22.07 30554 730 TCATCTTTTCTATAATCTC 3-2-1-7-2-2-2TCAtcTtttctatAAtcTC 730_1 -20.15 30555 730 TCATCTTTTCTATAATCTC3-1-1-8-1-3-2 TCAtCttttctatAatcTC 730_2 -20.09 30555 730TCATCTTTTCTATAATCTC 2-2-1-9-1-2-2 TCatCttttctataAtcTC 730_3 -18.83 30555730 TCATCTTTTCTATAATCTC 3-13-3 TCAtcttttctataatCTC 730_4 -20.65 30555730 TCATCTTTTCTATAATCTC 2-2-2-10-3 TCatCTtttctataatCTC 730_5 -21.3530555 731 GTCATCTTTTCTATAATC 1-1-1-2-1-6-3-1-2 GtCatCttttctATAaTC 731_1-19.76 30557 731 GTCATCTTTTCTATAATC 1-1-1-1-2-6-1-2-3 GtCaTCttttctAtaATC731_2 -19.19 30557 731 GTCATCTTTTCTATAATC 4-9-1-2-2 GTCAtcttttctaTaaTC731_3 -20.42 30557 731 GTCATCTTTTCTATAATC 3-2-1-8-4 GTCatCttttctatAATC731_4 -20.51 30557 731 GTCATCTTTTCTATAATC 1-1-4-10-2 GtCATCttttctataaTC731_5 -20.23 30557 732 TGTCATCTTTTCTATAAT 2-1-1-8-2-1-3TGtCatcttttcTAtAAT 732_1 -19.36 30558 732 TGTCATCTTTTCTATAAT2-1-2-7-2-2-2 TGtCAtcttttcTAtaAT 732_2 -20.51 30558 732TGTCATCTTTTCTATAAT 1-1-3-7-1-3-2 TgTCAtcttttcTataAT 732_3 -19.51 30558732 TGTCATCTTTTCTATAAT 4-10-4 TGTCatcttttctaTAAT 732_4 -21.42 30558 732TGTCATCTTTTCTATAAT 2-2-1-9-4 TGtcAtcttttctaTAAT 732_5 -18.57 30558 733ACTTAATTATACTTCCA 5-6-2-2-2 ACTTAattataCTtcCA 733_1 -21.55 30664 733ACTTAATTATACTTCCA 2-1-2-6-1-2-3 ACtTAattataCttCCA 733_2 -21.02 30664 733ACTTAATTATACTTCCA 1-2-2-7-5 ActTAattatacTTCCA 733_3 -20.65 30664 733ACTTAATTATACTTCCA 4-8-1-1-3 ACTTaattatacTtCCA 733_4 -21.09 30664 733ACTTAATTATACTTCCA 1-1-1-1-1-8-4 AcTtAattatactTCCA 733_5 -18.37 30664 734CACTTAATTATACTTCC 2-1-2-6-2-2-2 CAcTTaattatACttCC 734_1 -20.10 30665 734CACTTAATTATACTTCC 5-6-1-2-3 CACTTaattatActTCC 734_2 -21.76 30665 734CACTTAATTATACTTCC 1-1-1-1-1-7-2-1-2 CaCtTaattataCTtCC 734_3 -19.09 30665734 CACTTAATTATACTTCC 1-1-3-7-1-1-3 CaCTTaattataCtTCC 734_4 -20.59 30665734 CACTTAATTATACTTCC 2-1-2-8-4 CAcTTaattatacTTCC 734_5 -20.52 30665 735CACTTAATTATACTTCCA 2-2-1-7-2-1-3 CActTaattataCTtCCA 735_1 -22.96 30664735 CACTTAATTATACTTCCA 2-1-1-1-1-6-1-3-2 CAcTtAattataCttcCA 735_2 -19.3130664 735 CACTTAATTATACTTCCA 1-1-3-8-1-1-3 CaCTTaattatacTtCCA 735_3-22.43 30664 735 CACTTAATTATACTTCCA 1-1-1-1-2-7-1-2-2 CaCtTAattatacTtcCA735_4 -19.51 30664 735 CACTTAATTATACTTCCA 2-2-1-9-4 CActTaattatactTCCA735_5 -21.76 30664 736 ACACTTAATTATACTTCCA 1-1-2-1-1-6-2-3-2AcACtTaattatACttcCA 736_1 -20.93 30664 736 ACACTTAATTATACTTCCA2-2-1-7-1-1-1-2-2 ACacTtaattatAcTtcCA 736_2 -19.38 30664 736ACACTTAATTATACTTCCA 1-1-1-1-1-8-1-2-3 AcAcTtaattataCttCCA 736_3 -21.1030664 736 ACACTTAATTATACTTCCA 1-1-1-2-1-9-4 AcActTaattatactTCCA 736_4-21.31 30664 736 ACACTTAATTATACTTCCA 2-2-2-11-2 ACacTTaattatacttcCA736_5 -19.91 30664 737 ACACTTAATTATACTTCC 1-3-1-7-2-1-3AcacTtaattatACtTCC 737_1 -19.24 30665 737 ACACTTAATTATACTTCC1-1-1-1-2-6-2-2-2 AcAcTTaattatACttCC 737_2 -19.64 30665 737ACACTTAATTATACTTCC 2-1-2-7-1-1-1-1-2 ACaCTtaattatAcTtCC 737_3 -20.1230665 737 ACACTTAATTATACTTCC 3-2-1-8-4 ACActTaattatacTTCC 737_4 -21.5330665 737 ACACTTAATTATACTTCC 1-1-2-1-1-9-3 AcACtTaattatactTCC 737_5-19.40 30665 738 ACACTTAATTATACTTC 5-7-5 ACACTtaattatACTTC 738_1 -20.4730666 738 ACACTTAATTATACTTC 3-1-1-7-5 ACAcTtaattatACTTC 738_2 -18.4030666 738 ACACTTAATTATACTTC 2-1-2-7-5 ACaCTtaattatACTTC 738_3 -18.5130666 738 ACACTTAATTATACTTC 5-7-2-1-2 ACACTtaattatACtTC 738_4 -18.7730666 738 ACACTTAATTATACTTC 5-7-1-1-3 ACACTtaattatAcTTC 738_5 -18.4030666 738 ACACTTAATTATACTTC 5-8-4 ACACTtaattataCTTC 738_6 -19.88 30666739 TACACTTAATTATACTTCC 3-2-1-7-2-2-2 TACacTtaattatACttCC 739_1 -21.5730665 739 TACACTTAATTATACTTCC 1-4-1-7-1-1-4 TacacTtaattatAcTTCC 739_2-19.87 30665 739 TACACTTAATTATACTTCC 1-2-3-8-1-2-2 TacACTtaattataCttCC739_3 -20.88 30665 739 TACACTTAATTATACTTCC 4-11-4 TACActtaattatacTTCC739_4 -23.04 30665 739 TACACTTAATTATACTTCC 2-1-1-1-1-10-3TAcAcTtaattatactTCC 739_5 -20.03 30665 740 TACACTTAATTATACTTC 4-1-1-7-5TACAcTtaattatACTTC 740_1 -20.63 30666 740 TACACTTAATTATACTTC 3-1-2-7-5TACaCTtaattatACTTC 740_2 -20.74 30666 740 TACACTTAATTATACTTC 2-1-3-7-5TAcACTtaattatACTTC 740_3 -20.21 30666 740 TACACTTAATTATACTTC 3-1-2-8-4TACaCTtaattataCTTC 740_4 -20.14 30666 740 TACACTTAATTATACTTC 1-1-4-8-4TaCACTtaattataCTTC 740_5 -20.48 30666 741 TTACACTTAATTATACTTC2-1-2-7-4-1-2 TTaCActtaattATACtTC 741_1 -21.41 30666 741TTACACTTAATTATACTTC 5-7-3-1-3 TTACActtaattATAcTTC 741_2 -22.67 30666 741TTACACTTAATTATACTTC 4-1-1-6-2-1-4 TTACaCttaattATaCTTC 741_3 -22.54 30666741 TTACACTTAATTATACTTC 2-1-2-7-2-1-4 TTaCActtaattATaCTTC 741_4 -21.4830666 741 TTACACTTAATTATACTTC 5-7-1-1-5 TTACActtaattAtACTTC 741_5 -22.0430666 742 TTACACTTAATTATACTT 5-7-3-1-2 TTACActtaattATAcTT 742_1 -20.1830667 742 TTACACTTAATTATACTT 5-7-2-1-3 TTACActtaattATaCTT 742_2 -20.6230667 742 TTACACTTAATTATACTT 5-7-1-1-4 TTACActtaattAtACTT 742_3 -19.5430667 743 TTTACACTTAATTATACTT 4-1-1-6-4-1-2 TTTAcActtaatTATAcTT 743_1-21.26 30667 743 TTTACACTTAATTATACTT 3-1-2-6-3-1-3 TTTaCActtaatTATaCTT743_2 -22.57 30667 743 TTTACACTTAATTATACTT 4-8-2-1-4 TTTAcacttaatTAtACTT743_3 -20.48 30667 743 TTTACACTTAATTATACTT 1-1-4-6-2-2-3TtTACActtaatTAtaCTT 743_4 -21.20 30667 743 TTTACACTTAATTATACTT2-2-2-6-1-1-5 TTtaCActtaatTaTACTT 743_5 -21.02 30667 744TTTACACTTAATTATACT 3-1-2-6-3-1-2 TTTaCActtaatTATaCT 744_1 -20.75 30668744 TTTACACTTAATTATACT 1-1-4-6-3-1-2 TtTACActtaatTATaCT 744_2 -21.0630668 744 TTTACACTTAATTATACT 2-1-3-6-2-1-3 TTtACActtaatTAtACT 744_3-19.03 30668 744 TTTACACTTAATTATACT 4-8-1-1-4 TTTAcacttaatTaTACT 744_4-19.42 30668 744 TTTACACTTAATTATACT 1-1-1-1-2-6-1-1-4 TtTaCActtaatTaTACT744_5 -19.12 30668 745 ATTTACACTTAATTATACT 4-1-1-6-4-1-2ATTTaCacttaaTTATaCT 745_1 -22.20 30668 745 ATTTACACTTAATTATACT2-1-3-6-3-1-3 ATtTACacttaaTTAtACT 745_2 -21.43 30668 745ATTTACACTTAATTATACT 5-7-2-1-4 ATTTAcacttaaTTaTACT 745_3 -22.44 30668 745ATTTACACTTAATTATACT 1-2-3-6-2-1-4 AttTACacttaaTTaTACT 745_4 -20.95 30668745 ATTTACACTTAATTATACT 3-1-2-6-1-1-5 ATTTACacttaaTtATACT 745_5 -20.9230668 746 ATTTACACTTAATTATAC 5-8-5 ATTTAcacttaatTATAC 746_1 -19.94 30669746 ATTTACACTTAATTATAC 4-1-1-7-5 ATTTaCacttaatTATAC 746_2 -19.40 30669746 ATTTACACTTAATTATAC 2-1-3-7-5 ATtTACacttaatTATAC 746_3 -19.70 30669747 AATTTACACTTAATTATAC 3-1-2-6-3-1-3 AATtTAcacttaATTaTAC 747_1 -19.5130669 747 AATTTACACTTAATTATAC 1-1-4-6-3-1-3 AaTTTAcacttaATTaTAC 747_2-19.51 30669 747 AATTTACACTTAATTATAC 4-8-2-1-4 AATTtacacttaATTATAC 747_3-18.04 30669 747 AATTTACACTTAATTATAC 5-7-1-1-5 AATTTacacttaAtTATAC 747_4-19.79 30669 747 AATTTACACTTAATTATAC 2-1-3-6-1-1-5 AAtTTAcacttaAtTATAC747_5 -19.26 30669 748 AATTTACACTTAATTATACT 3-2-2-6-4-1-2AATttACacttaaTTATaCT 748_1 -21.50 30668 748 AATTTACACTTAATTATACT5-1-1-6-3-1-3 AATTTaCacttaaTTAtACT 748_2 -21.87 30668 748AATTTACACTTAATTATACT 3-1-3-6-2-1-4 AATtTACacttaaTTaTACT 748_3 -22.9530668 748 AATTTACACTTAATTATACT 1-1-4-7-2-1-1-1-2 AaTTTAcacttaaTTaTaCT748_4 -20.23 30668 748 AATTTACACTTAATTATACT 2-1-2-1-1-6-1-1-5AAtTTaCacttaaTtATACT 748_5 -20.55 30668 749 TAATTTACACTTAATTATAC2-1-4-6-4-1-2 TAaTTTAcacttaATTAtAC 749_1 -20.98 30669 749TAATTTACACTTAATTATAC 5-8-3-1-3 TAATTtacacttaATTaTAC 749_2 -20.60 30669749 TAATTTACACTTAATTATAC 2-2-3-6-3-1-3 TAatTTAcacttaATTaTAC 749_3 -20.8030669 749 TAATTTACACTTAATTATAC 4-1-2-6-2-1-4 TAATtTAcacttaATTATAC 749_4-21.41 30669 749 TAATTTACACTTAATTATAC 1-1-1-1-2-7-1-1-5TaAtTTacacttaAtTATAC 749_5 -18.92 30669 750 TAATTTACACTTAATTAT 5-8-5TAATTtacacttaATTAT 750_1 -18.27 30671 750 TAATTTACACTTAATTAT 4-1-1-7-5TAATtTacacttaATTAT 750_2 -18.18 30671 750 TAATTTACACTTAATTAT 2-1-3-7-5TAaTTTacacttaATTAT 750_3 -18.18 30671 750 TAATTTACACTTAATTAT 1-1-4-7-5TaATTTacacttaATTAT 750_4 -18.16 30671 751 TAATTTACACTTAATTATA 5-7-4-1-2TAATTtacacttAATTaTA 751_1 -18.87 30670 751 TAATTTACACTTAATTATA 5-7-2-1-4TAATTtacacttAAtTATA 751_2 -19.05 30670 751 TAATTTACACTTAATTATA3-1-2-6-2-1-4 TAAtTTacacttAAtTATA 751_3 -18.54 30670 751TAATTTACACTTAATTATA 4-1-1-6-1-1-5 TAATtTacacttAaTTATA 751_4 -19.40 30670751 TAATTTACACTTAATTATA 2-1-3-6-1-1-5 TAaTTTacacttAaTTATA 751_5 -19.4130670 752 TTAATTTACACTTAATTATA 3-1-3-6-4-1-2 TTAaTTTacacttAATTaTA 752_1-20.61 30670 752 TTAATTTACACTTAATTATA 5-1-1-6-3-1-3 TTAATtTacacttAATtATA752_2 -20.28 30670 752 TTAATTTACACTTAATTATA 2-1-4-6-2-1-4TTaATTTacacttAAtTATA 752_3 -20.77 30670 752 TTAATTTACACTTAATTATA3-2-2-6-1-1-5 TTAatTTacacttAaTTATA 752_4 -20.28 30670 752TTAATTTACACTTAATTATA 4-1-1-8-1-1-4 TTAAtTtacacttaAtTATA 752_5 -18.8030670 753 TTAATTTACACTTAATTAT 4-1-1-6-3-1-3 TTAAtTtacactTAAtTAT 753_1-18.65 30671 753 TTAATTTACACTTAATTAT 3-1-2-6-2-1-4 TTAaTTtacactTAaTTAT753_2 -19.52 30671 753 TTAATTTACACTTAATTAT 2-1-2-7-2-1-4TTaATttacactTAaTTAT 753_3 -18.68 30671 753 TTAATTTACACTTAATTAT 5-7-1-1-5TTAATttacactTaATTAT 753_4 -20.00 30671 753 TTAATTTACACTTAATTAT2-1-3-6-1-1-5 TTaATTtacactTaATTAT 753_5 -19.47 30671 754TTTAATTTACACTTAATTA 3-1-2-6-3-1-3 TTTaATttacacTTAaTTA 754_1 -19.46 30672754 TTTAATTTACACTTAATTA 5-7-2-1-4 TTTAAtttacacTTaATTA 754_2 -19.54 30672754 TTTAATTTACACTTAATTA 4-1-1-6-2-1-4 TTTAaTttacacTTaATTA 754_3 -19.4630672 754 TTTAATTTACACTTAATTA 1-1-1-1-2-6-2-1-4 TtTaATttacacTTaATTA754_4 -18.11 30672 754 TTTAATTTACACTTAATTA 1-1-4-7-3-1-2TtTAATttacactTAAtTA 754_5 -18.02 30672 755 TTTAATTTACACTTAATTAT4-1-2-6-3-1-3 TTTAaTTtacactTAAtTAT 755_1 -20.90 30671 755TTTAATTTACACTTAATTAT 3-1-2-7-2-1-4 TTTaATttacactTAaTTAT 755_2 -20.5030671 755 TTTAATTTACACTTAATTAT 1-1-5-6-2-1-4 TtTAATTtacactTAaTTAT 755_3-21.34 30671 755 TTTAATTTACACTTAATTAT 5-8-1-1-5 TTTAAtttacactTaATTAT755_4 -20.58 30671 755 TTTAATTTACACTTAATTAT 2-2-3-6-1-1-5TTtaATTtacactTaATTAT 755_5 -20.05 30671 756 ATTTAATTTACACTTAATTA5-1-1-6-4-1-2 ATTTAaTttacacTTAAtTA 756_1 -21.11 30672 756ATTTAATTTACACTTAATTA 3-2-2-6-3-1-3 ATTtaATttacacTTAaTTA 756_2 -20.2930672 756 ATTTAATTTACACTTAATTA 4-1-2-6-2-1-4 ATTTaATttacacTTaATTA 756_3-21.50 30672 756 ATTTAATTTACACTTAATTA 2-1-4-6-2-2-3 ATtTAATttacacTTaaTTA756_4 -20.39 30672 756 ATTTAATTTACACTTAATTA 2-1-4-8-5ATtTAATttacacttAATTA 756_5 -20.08 30672 757 ATTTAATTTACACTTAATT5-7-3-1-3 ATTTAatttacaCTTaATT 757_1 -20.52 30673 757 ATTTAATTTACACTTAATT4-1-1-7-2-1-3 ATTTaAtttacacTTaATT 757_2 -18.02 30673 757ATTTAATTTACACTTAATT 2-1-3-7-2-1-3 ATtTAAtttacacTTaATT 757_3 -18.04 30673757 ATTTAATTTACACTTAATT 4-1-1-8-5 ATTTaAtttacactTAATT 757_4 -18.34 30673757 ATTTAATTTACACTTAATT 2-1-3-8-5 ATtTAAtttacactTAATT 757_5 -18.37 30673758 TATTTAATTTACACTTAAT 3-1-2-6-4-1-2 TATtTAatttacACTTaAT 758_1 -20.1630674 758 TATTTAATTTACACTTAAT 2-1-3-6-2-1-4 TAtTTAatttacACtTAAT 758_2-19.37 30674 758 TATTTAATTTACACTTAAT 1-1-4-6-2-1-4 TaTTTAatttacACtTAAT758_3 -19.19 30674 758 TATTTAATTTACACTTAAT 3-1-2-6-1-1-5TATtTAatttacAcTTAAT 758_4 -19.44 30674 758 TATTTAATTTACACTTAAT2-1-3-6-1-1-5 TAtTTAatttacAcTTAAT 758_5 -19.00 30674 759TATTTAATTTACACTTAATT 2-1-4-6-4-1-2 TAtTTAAtttacaCTTAaTT 759_1 -21.5430673 759 TATTTAATTTACACTTAATT 5-1-1-6-3-1-3 TATTTaAtttacaCTTaATT 759_2-21.92 30673 759 TATTTAATTTACACTTAATT 4-1-2-7-3-1-2 TATTTAAtttacacTTAaTT759_3 -19.35 30673 759 TATTTAATTTACACTTAATT 3-1-3-7-2-1-3TATtTAAtttacacTTaATT 759_4 -20.28 30673 759 TATTTAATTTACACTTAATT2-1-4-8-5 TAtTTAAtttacactTAATT 759_5 -20.16 30673 760 CTATTTAATTTACACTT5-6-1-1-4 CTATTtaatttAcACTT 760_1 -19.07 30677 760 CTATTTAATTTACACTT5-7-5 CTATTtaatttaCACTT 760_2 -20.97 30677 760 CTATTTAATTTACACTT2-2-1-7-5 CTatTtaatttaCACTT 760_3 -18.08 30677 760 CTATTTAATTTACACTT5-7-2-1-2 CTATTtaatttaCAcTT 760_4 -18.90 30677 760 CTATTTAATTTACACTT5-7-1-1-3 CTATTtaatttaCaCTT 760_5 -19.01 30677 761 CTATTTAATTTACACTTAA2-1-3-6-4-1-2 CTaTTTaatttaCACTTAA 761_1 -20.98 30675 761CTATTTAATTTACACTTAA 3-1-2-6-3-1-3 CTAtTTaatttaCACtTAA 761_2 -21.73 30675761 CTATTTAATTTACACTTAA 4-1-1-6-2-1-4 CTATtTaatttaCAcTTAA 761_3 -21.8030675 761 CTATTTAATTTACACTTAA 5-7-2-2-3 CTATTtaatttaCActTAA 761_4 -20.8630675 761 CTATTTAATTTACACTTAA 2-1-3-6-1-1-5 CTaTTTaatttaCaCTTAA 761_5-21.29 30675 762 CTATTTAATTTACACTTA 5-7-3-1-2 CTATTtaatttaCACtTA 762_1-21.50 30676 762 CTATTTAATTTACACTTA 3-2-1-6-3-1-2 CTAttTaatttaCACtTA762_2 -20.17 30676 762 CTATTTAATTTACACTTA 3-1-1-7-2-1-3CTAtTtaatttaCAcTTA 762_3 -19.37 30676 762 CTATTTAATTTACACTTA2-1-3-6-2-1-3 CTaTTTaatttaCAcTTA 762_4 -20.43 30676 762CTATTTAATTTACACTTA 2-1-3-6-1-1-4 CTaTTTaatttaCaCTTA 762_5 -20.54 30676763 CTATTTAATTTACACTTAAT 2-1-4-6-3-2-2 CTaTTTAatttacACTtaAT 763_1 -21.7930674 763 CTATTTAATTTACACTTAAT 4-1-2-6-2-1-4 CTATtTAatttacACtTAAT 763_2-23.29 30674 763 CTATTTAATTTACACTTAAT 1-2-4-6-1-1-5 CtaTTTAatttacAcTTAAT763_3 -20.68 30674 763 CTATTTAATTTACACTTAAT 3-1-3-6-1-1-2-1-2CTAtTTAatttacAcTTaAT 763_4 -21.14 30674 763 CTATTTAATTTACACTTAAT5-1-1-7-3-1-2 CTATTtAatttacaCTTaAT 763_5 -22.14 30674 764TCTATTTAATTTACACTTA 2-1-3-6-4-1-2 TCtATTtaatttACACtTA 764_1 -21.94 30676764 TCTATTTAATTTACACTTA 4-1-1-6-3-1-3 TCTAtTtaatttACAcTTA 764_2 -22.4730676 764 TCTATTTAATTTACACTTA 3-1-2-7-2-1-3 TCTaTTtaatttaCAcTTA 764_3-21.69 30676 764 TCTATTTAATTTACACTTA 1-1-4-7-2-2-2 TcTATTtaatttaCActTA764_4 -20.33 30676 764 TCTATTTAATTTACACTTA 3-2-1-7-1-1-4TCTatTtaatttaCaCTTA 764_5 -20.85 30676 765 TCTATTTAATTTACACTT3-2-1-6-2-1-3 TCTatTtaatttACaCTT 765_1 -19.21 30677 765TCTATTTAATTTACACTT 3-1-2-7-5 TCTaTTtaatttaCACTT 765_2 -21.53 30677 765TCTATTTAATTTACACTT 2-1-3-7-5 TCtATTtaatttaCACTT 765_3 -20.81 30677 765TCTATTTAATTTACACTT 4-1-1-7-2-1-2 TCTAtTtaatttaCAcTT 765_4 -19.64 30677765 TCTATTTAATTTACACTT 1-1-4-7-2-1-2 TcTATTtaatttaCAcTT 765_5 -19.1230677 766 TCTATTTAATTTACACTTAA 2-1-2-1-1-6-3-2-2 TCtATtTaatttaCACttAA766_1 -20.25 30675 766 TCTATTTAATTTACACTTAA 4-1-1-7-2-1-4TCTAtTtaatttaCAcTTAA 766_2 -22.62 30675 766 TCTATTTAATTTACACTTAA1-1-1-1-3-6-2-2-3 TcTaTTTaatttaCActTAA 766_3 -20.38 30675 766TCTATTTAATTTACACTTAA 3-1-2-7-1-1-2-1-2 TCTaTTtaatttaCaCTTAA 766_4 -20.2730675 766 TCTATTTAATTTACACTTAA 2-3-2-6-1-1-1-1-3 TCtatTTaatttaCaCtTAA766_5 -19.51 30675 767 ATCTATTTAATTTACACTT 2-1-2-7-4-1-2ATcTAtttaattTACAcTT 767_1 -21.49 30677 767 ATCTATTTAATTTACACTT1-1-4-6-3-1-3 AtCTATttaattTACaCTT 767_2 -23.18 30677 767ATCTATTTAATTTACACTT 4-1-1-6-2-1-4 ATCTaTttaattTAcACTT 767_3 -22.64 30677767 ATCTATTTAATTTACACTT 5-7-2-2-3 ATCTAtttaattTAcaCTT 767_4 -22.78 30677767 ATCTATTTAATTTACACTT 1-1-4-6-1-1-5 AtCTATttaattTaCACTT 767_5 -23.5230677 768 ATCTATTTAATTTACACTTA 1-2-4-6-2-1-1-1-2 AtcTATTtaatttACaCtTA768_1 -21.10 30676 768 ATCTATTTAATTTACACTTA 1-1-3-1-1-6-1-1-5AtCTAtTtaatttAcACTTA 768_2 -22.17 30676 768 ATCTATTTAATTTACACTTA3-2-2-6-1-1-2-1-2 ATCtaTTtaatttAcACtTA 768_3 -20.60 30676 768ATCTATTTAATTTACACTTA 1-1-2-1-2-7-2-2-2 AtCTaTTtaatttaCActTA 768_4 -20.8030676 768 ATCTATTTAATTTACACTTA 3-1-1-1-1-7-1-2-3 ATCtAtTtaatttaCacTTA768_5 -19.72 30676 769 TATCTATTTAATTTACACTT 1-1-2-1-2-6-4-1-2TaTCTATttaattTACAcTT 769_1 -22.65 30677 769 TATCTATTTAATTTACACTT2-1-1-1-2-6-2-1-4 TAtCtATttaattTAcACTT 769_2 -22.23 30677 769TATCTATTTAATTTACACTT 2-1-4-6-2-3-2 TAtCTATttaattTAcacTT 769_3 -22.6630677 769 TATCTATTTAATTTACACTT 1-3-3-6-1-1-5 TatcTATttaattTaCACTT 769_4-22.96 30677 769 TATCTATTTAATTTACACTT 1-1-3-1-1-6-1-3-3TaTCTaTttaattTacaCTT 769_5 -21.15 30677 770 TATCTATTTAATTTACACT2-1-3-6-3-1-3 TAtCTAtttaatTTAcACT 770_1 -22.62 30678 770TATCTATTTAATTTACACT 1-1-4-6-3-1-3 TaTCTAtttaatTTAcACT 770_2 -22.62 30678770 TATCTATTTAATTTACACT 2-2-2-6-2-1-4 TAtcTAtttaatTTaCACT 770_3 -21.8430678 770 TATCTATTTAATTTACACT 1-2-3-6-1-1-5 TatCTAtttaatTtACACT 770_4-21.72 30678 770 TATCTATTTAATTTACACT 4-1-1-7-2-1-3 TATCtAtttaattTAcACT770_5 -21.09 30678 771 TTATCTATTTAATTTACACT 2-4-1-6-4-1-2TTatctAtttaatTTACaCT 771_1 -20.22 30678 771 TTATCTATTTAATTTACACT2-2-3-6-3-2-2 TTatCTAtttaatTTAcaCT 771_2 -22.76 30678 771TTATCTATTTAATTTACACT 1-1-5-6-2-2-3 TtATCTAtttaatTTacACT 771_3 -22.8730678 771 TTATCTATTTAATTTACACT 2-2-3-6-1-2-4 TTatCTAtttaatTtaCACT 771_4-22.94 30678 771 TTATCTATTTAATTTACACT 5-1-1-7-1-2-3 TTATCtAtttaattTacACT771_5 -21.68 30678 772 TTTATCTATTTAATTTACA 1-1-3-7-4-1-2TtTATctatttaATTTaCA 772_1 -19.96 30680 772 TTTATCTATTTAATTTACA4-1-1-6-3-2-2 TTTAtCtatttaATTtaCA 772_2 -19.70 30680 772TTTATCTATTTAATTTACA 3-1-2-6-2-1-4 TTTaTCtatttaATtTACA 772_3 -21.24 30680772 TTTATCTATTTAATTTACA 5-7-2-2-3 TTTATctatttaATttACA 772_4 -19.82 30680772 TTTATCTATTTAATTTACA 1-1-4-6-1-1-5 TtTATCtatttaAtTTACA 772_5 -21.4230680 773 TTTTATCTATTTAATTTAC 2-1-3-6-3-1-3 TTtTATctatttAATtTAC 773_1-19.10 30681 773 TTTTATCTATTTAATTTAC 1-1-4-6-2-1-4 TtTTATctatttAAtTTAC773_2 -18.66 30681 773 TTTTATCTATTTAATTTAC 3-1-2-6-1-1-5TTTTATctatttAaTTTAC 773_3 -18.15 30681 773 TTTTATCTATTTAATTTAC1-2-3-6-1-1-5 TttTATctatttAaTTTAC 773_4 -18.29 30681 773TTTTATCTATTTAATTTAC 2-1-3-6-1-2-4 TTtTATctatttAatTTAC 773_5 -18.15 30681774 TTTTATCTATTTAATTTACA 1-1-2-1-1-7-4-1-2 TtTTaTctatttaATTTaCA 774_1-19.84 30680 774 TTTTATCTATTTAATTTACA 2-1-1-1-2-6-3-1-3TTtTaTCtatttaATTTACA 774_2 -20.79 30680 774 TTTTATCTATTTAATTTACA4-2-1-6-2-1-4 TTTTatCtatttaATtTACA 774_3 -21.94 30680 774TTTTATCTATTTAATTTACA 1-1-5-6-2-3-2 TtTTATCtatttaATttaCA 774_4 -21.3230680 774 TTTTATCTATTTAATTTACA 2-2-3-6-1-2-4 TTttATCtatttaAttTACA 774_5-20.67 30680 775 CTTTTATCTATTTAATTTA 5-7-4-1-2 CTTTTatctattTAATtTA 775_1-21.18 30682 775 CTTTTATCTATTTAATTTA 5-7-2-1-4 CTTTTatctattTAaTTTA 775_2-21.18 30682 775 CTTTTATCTATTTAATTTA 5-7-2-2-3 CTTTTatctattTAatTTA 775_3-20.23 30682 775 CTTTTATCTATTTAATTTA 3-1-1-7-1-1-5 CTTtTatctattTaATTTA775_4 -19.83 30682 775 CTTTTATCTATTTAATTTA 2-1-2-7-1-1-1-1-3CTtTTatctattTaAtTTA 775_5 -18.07 30682 776 CTTTTATCTATTTAATTTAC1-1-5-6-4-1-2 CtTTTATctatttAATTTAC 776_1 -21.25 30681 776CTTTTATCTATTTAATTTAC 3-1-1-8-3-1-3 CTTtTatctatttAATtTAC 776_2 -20.1330681 776 CTTTTATCTATTTAATTTAC 5-8-2-1-4 CTTTTatctatttAAtTTAC 776_3-21.02 30681 776 CTTTTATCTATTTAATTTAC 1-1-2-1-2-6-2-1-4CtTTTATctatttAAtTTAC 776_4 -19.49 30681 776 CTTTTATCTATTTAATTTAC2-1-4-6-2-2-3 CTtTTATctatttAAttTAC 776_5 -21.33 30681 777ACTTTTATCTATTTAATTT 4-1-1-6-4-1-2 ACTTtTatctatTTAAtTT 777_1 -20.04 30683777 ACTTTTATCTATTTAATTT 3-1-2-6-3-1-3 ACTtTTatctatTTAaTTT 777_2 -20.4830683 777 ACTTTTATCTATTTAATTT 5-7-2-1-4 ACTTTtatctatTTaATTT 777_3 -20.5430683 777 ACTTTTATCTATTTAATTT 2-2-2-6-2-1-4 ACttTTatctatTTaATTT 777_4-19.26 30683 777 ACTTTTATCTATTTAATTT 4-1-1-6-1-2-4 ACTTtTatctatTtaATTT777_5 -19.21 30683 778 ACTTTTATCTATTTAATTTA 2-3-1-7-4-1-2ACtttTatctattTAATtTA 778_1 -19.89 30682 778 ACTTTTATCTATTTAATTTA1-1-4-7-2-1-1-1-2 AcTTTTatctattTAaTtTA 778_2 -19.82 30682 778ACTTTTATCTATTTAATTTA 3-2-1-7-2-2-3 ACTttTatctattTAatTTA 778_3 -20.1330682 778 ACTTTTATCTATTTAATTTA 4-9-1-1-5 ACTTttatctattTaATTTA 778_4-21.14 30682 778 ACTTTTATCTATTTAATTTA 2-1-3-7-1-1-5 ACtTTTatctattTaATTTA778_5 -21.49 30682 779 ACTTTTATCTATTTAATT 2-1-3-6-2-1-3ACtTTTatctatTTaATT 779_1 -18.25 30684 779 ACTTTTATCTATTTAATT 4-1-1-7-5ACTTtTatctattTAATT 779_2 -19.17 30684 779 ACTTTTATCTATTTAATT 3-1-2-7-5ACTtTTatctattTAATT 779_3 -19.17 30684 779 ACTTTTATCTATTTAATT 2-1-3-7-5ACtTTTatctattTAATT 779_4 -18.79 30684 779 ACTTTTATCTATTTAATT 1-1-4-7-5AcTTTTatctattTAATT 779_5 -18.42 30684 780 AACTTTTATCTATTTAATT 5-7-3-1-3AACTTttatctaTTTaATT 780_1 -19.61 30684 780 AACTTTTATCTATTTAATT 5-8-3-1-2AACTTttatctatTTAaTT 780_2 -18.68 30684 780 AACTTTTATCTATTTAATT4-1-1-7-3-1-2 AACTtTtatctatTTAaTT 780_3 -18.17 30684 780AACTTTTATCTATTTAATT 1-1-4-7-2-1-3 AaCTTTtatctatTTaATT 780_4 -18.45 30684780 AACTTTTATCTATTTAATT 5-9-5 AACTTttatctattTAATT 780_5 -19.19 30684 781AACTTTTATCTATTTAAT 5-8-5 AACTTttatctatTTAAT 781_1 -18.18 30685 782AACTTTTATCTATTTAATTT 1-1-1-1-3-6-4-1-2 AaCtTTTatctatTTAAtTT 782_1 -19.4030683 782 AACTTTTATCTATTTAATTT 4-2-1-6-3-1-3 AACTttTatctatTTAaTTT 782_2-20.41 30683 782 AACTTTTATCTATTTAATTT 5-1-1-6-2-1-4 AACTTtTatctatTTaATTT782_3 -21.20 30683 782 AACTTTTATCTATTTAATTT 2-1-4-6-1-2-4AAcTTTTatctatTtaATTT 782_4 -19.21 30683 782 AACTTTTATCTATTTAATTT1-1-2-1-2-7-2-1-3 AaCTtTTatctattTAaTTT 782_5 -19.40 30683 783TAACTTTTATCTATTTAAT 2-1-3-6-4-1-2 TAaCTTttatctATTTaAT 783_1 -19.91 30685783 TAACTTTTATCTATTTAAT 2-1-3-6-2-1-4 TAaCTTttatctATtTAAT 783_2 -19.9330685 783 TAACTTTTATCTATTTAAT 5-7-2-1-1-1-2 TAACTtttatctATtTaAT 783_3-18.79 30685 783 TAACTTTTATCTATTTAAT 1-1-4-6-1-1-5 TaACTTttatctAtTTAAT783_4 -19.16 30685 783 TAACTTTTATCTATTTAAT 5-9-5 TAACTtttatctatTTAAT783_5 -19.60 30685 784 TAACTTTTATCTATTTAATT 4-1-1-7-1-1-2-1-2TAACtTttatctaTtTAaTT 784_1 -18.83 30684 784 TAACTTTTATCTATTTAATT2-1-4-7-3-1-2 TAaCTTTtatctatTTAaTT 784_2 -20.71 30684 784TAACTTTTATCTATTTAATT 2-1-3-8-2-1-3 TAaCTTttatctatTTaATT 784_3 -19.8730684 784 TAACTTTTATCTATTTAATT 1-1-5-7-2-1-3 TaACTTTtatctatTTaATT 784_4-20.35 30684 784 TAACTTTTATCTATTTAATT 5-10-5 TAACTtttatctattTAATT 784_5-20.61 30684 785 TAACTTTTATCTATTTAA 5-7-2-1-3 TAACTtttatctATtTAA 785_1-18.07 30686 786 ATAACTTTTATCTATTTAA 3-1-2-6-4-1-2 ATAaCTtttatcTATTtAA786_1 -20.14 30686 786 ATAACTTTTATCTATTTAA 4-1-1-6-3-1-3ATAAcTtttatcTATtTAA 786_2 -20.03 30686 786 ATAACTTTTATCTATTTAA2-1-3-6-2-1-4 ATaACTtttatcTAtTTAA 786_3 -20.33 30686 786ATAACTTTTATCTATTTAA 3-1-2-6-2-2-3 ATAaCTtttatcTAttTAA 786_4 -19.84 30686786 ATAACTTTTATCTATTTAA 5-7-1-1-5 ATAACttttatcTaTTTAA 786_5 -20.30 30686787 ATAACTTTTATCTATTTAAT 3-1-3-6-3-2-2 ATAaCTTttatctATTtaAT 787_1 -20.7330685 787 ATAACTTTTATCTATTTAAT 2-1-4-6-2-1-4 ATaACTTttatctATtTAAT 787_2-21.66 30685 787 ATAACTTTTATCTATTTAAT 3-1-2-7-1-2-4 ATAaCTtttatctAttTAAT787_3 -19.93 30685 787 ATAACTTTTATCTATTTAAT 4-2-1-7-3-1-2ATAActTttatctaTTTaAT 787_4 -18.98 30685 787 ATAACTTTTATCTATTTAAT2-1-4-8-5 ATaACTTttatctatTTAAT 787_5 -21.13 30685 788TATAACTTTTATCTATTTA 1-1-2-1-1-6-4-1-2 TaTAaCttttatCTATtTA 788_1 -21.1030687 788 TATAACTTTTATCTATTTA 2-2-2-6-3-1-3 TAtaACttttatCTAtTTA 788_2-20.60 30687 788 TATAACTTTTATCTATTTA 3-1-2-6-2-1-4 TATaACttttatCTaTTTA788_3 -22.09 30687 788 TATAACTTTTATCTATTTA 5-7-1-1-5 TATAActtttatCtATTTA788_4 -21.33 30687 788 TATAACTTTTATCTATTTA 4-1-1-7-2-2-2TATAaCttttatcTAttTA 788_5 -20.13 30687 789 TATAACTTTTATCTATTTAA4-1-1-7-4-1-2 TATAaCttttatcTATTTAA 789_1 -21.18 30686 789TATAACTTTTATCTATTTAA 2-2-3-6-3-1-3 TAtaACTtttatcTATtTAA 789_2 -21.3230686 789 TATAACTTTTATCTATTTAA 1-1-5-6-2-1-4 TaTAACTtttatcTAtTTAA 789_3-21.97 30686 789 TATAACTTTTATCTATTTAA 3-1-2-7-1-1-1-1-3TATaACttttatcTaTtTAA 789_4 -19.86 30686 789 TATAACTTTTATCTATTTAA4-2-1-6-1-2-4 TATAacTtttatcTatTTAA 789_5 -20.09 30686 790TTATAACTTTTATCTATTT 2-1-3-6-4-1-2 TTaTAActtttaTCTAtTT 790_1 -21.00 30688790 TTATAACTTTTATCTATTT 5-7-2-2-3 TTATAacttttaTCtaTTT 790_2 -20.52 30688790 TTATAACTTTTATCTATTT 4-1-1-6-1-1-5 TTATaActtttaTcTATTT 790_3 -21.0830688 790 TTATAACTTTTATCTATTT 4-1-1-7-3-1-2 TTATaActtttatCTAtTT 790_4-20.46 30688 790 TTATAACTTTTATCTATTT 2-1-3-8-5 TTaTAActtttatcTATTT 790_5-19.98 30688 791 TTATAACTTTTATCTATT 5-7-3-1-2 TTATAacttttaTCTaTT 791_1-20.32 30689 791 TTATAACTTTTATCTATT 5-7-1-1-4 TTATAacttttaTcTATT 791_2-19.99 30689 791 TTATAACTTTTATCTATT 4-1-1-7-5 TTATaActtttatCTATT 791_3-20.40 30689 791 TTATAACTTTTATCTATT 4-9-5 TTATaacttttatCTATT 791_4-19.98 30689 791 TTATAACTTTTATCTATT 2-1-3-7-5 TTaTAActtttatCTATT 791_5-19.81 30689 792 TTATAACTTTTATCTATTTA 1-2-1-1-2-6-3-2-2TtaTaACttttatCTAttTA 792_1 -20.10 30687 792 TTATAACTTTTATCTATTTA3-2-1-7-1-1-2-1-2 TTAtaActtttatCtATtTA 792_2 -18.80 30687 792TTATAACTTTTATCTATTTA 4-1-2-6-1-3-3 TTATaACttttatCtatTTA 792_3 -21.3430687 792 TTATAACTTTTATCTATTTA 2-1-2-1-1-7-2-1-3 TTaTAaCttttatcTAtTTA792_4 -20.83 30687 792 TTATAACTTTTATCTATTTA 1-1-4-8-1-1-4TtATAActtttatcTaTTTA 792_5 -19.94 30687 793 CTTATAACTTTTATCTATT1-1-1-1-2-6-3-2-2 CtTaTAacttttATCtaTT 793_1 -19.45 30689 793CTTATAACTTTTATCTATT 1-2-3-6-1-1-5 CttATAacttttAtCTATT 793_2 -21.25 30689793 CTTATAACTTTTATCTATT 3-2-1-8-5 CTTatAacttttatCTATT 793_3 -20.78 30689793 CTTATAACTTTTATCTATT 1-1-3-9-2-1-2 CtTATaacttttatCTaTT 793_4 -19.8230689 793 CTTATAACTTTTATCTATT 5-9-1-1-3 CTTATaacttttatCtATT 793_5 -20.8130689 794 CTTATAACTTTTATCTAT 5-7-3-1-2 CTTATaacttttATCtAT 794_1 -21.0230690 794 CTTATAACTTTTATCTAT 1-1-3-7-1-1-4 CtTATaacttttAtCTAT 794_2-20.04 30690 794 CTTATAACTTTTATCTAT 2-2-1-8-5 CTtaTaacttttaTCTAT 794_3-19.59 30690 794 CTTATAACTTTTATCTAT 3-1-2-8-4 CTTaTAacttttatCTAT 794_4-20.86 30690 794 CTTATAACTTTTATCTAT 5-10-3 CTTATaacttttatcTAT 794_5-19.99 30690 795 CTTATAACTTTTATCTATTT 1-1-1-2-2-6-2-1-1-1-2CtTatAActtttaTCtAtTT 795_1 -18.22 30688 795 CTTATAACTTTTATCTATTT1-1-1-1-2-8-2-1-3 CtTaTAacttttatCTaTTT 795_2 -20.86 30688 795CTTATAACTTTTATCTATTT 2-1-2-1-1-7-2-2-2 CTtATaActtttatCTatTT 795_3 -20.5430688 795 CTTATAACTTTTATCTATTT 3-2-1-8-1-1-1-1-2 CTTatAacttttatCtAtTT795_4 -18.19 30688 795 CTTATAACTTTTATCTATTT 1-2-2-1-1-9-4CttATaActtttatctATTT 795_5 -18.61 30688 796 CTTATAACTTTTATCTA 5-6-2-1-3CTTATaactttTAtCTA 796_1 -21.44 30691 796 CTTATAACTTTTATCTA 5-6-1-2-3CTTATaactttTatCTA 796_2 -20.31 30691 796 CTTATAACTTTTATCTA 1-1-3-7-5CtTATaacttttATCTA 796_3 -19.90 30691 796 CTTATAACTTTTATCTA 3-1-1-8-4CTTaTaacttttaTCTA 796_4 -18.77 30691 796 CTTATAACTTTTATCTA 2-1-2-8-4CTtATaacttttaTCTA 796_5 -18.43 30691 797 GCTTATAACTTTTATCTA2-2-2-6-2-2-2 GCttATaactttTAtcTA 797_1 -21.32 30691 797GCTTATAACTTTTATCTA 4-9-1-1-3 GCTTataacttttAtCTA 797_2 -21.88 30691 797GCTTATAACTTTTATCTA 2-12-4 GCttataacttttaTCTA 797_3 -20.47 30691 797GCTTATAACTTTTATCTA 2-1-1-1-1-9-3 GCtTaTaacttttatCTA 797_4 -20.94 30691797 GCTTATAACTTTTATCTA 1-1-4-10-2 GcTTATaacttttatcTA 797_5 -19.62 30691798 GCTTATAACTTTTATCT 2-9-1-2-3 GCttataacttTtaTCT 798_1 -18.54 30692 798GCTTATAACTTTTATCT 2-10-5 GCttataactttTATCT 798_2 -20.90 30692 798GCTTATAACTTTTATCT 4-8-1-1-3 GCTTataactttTaTCT 798_3 -21.40 30692 798GCTTATAACTTTTATCT 2-1-2-8-4 GCtTAtaacttttATCT 798_4 -21.00 30692 798GCTTATAACTTTTATCT 5-10-2 GCTTAtaacttttatCT 798_5 -20.68 30692 799TGCTTATAACTTTTATC 3-8-3-1-2 TGCttataactTTTaTC 799_1 -19.59 30693 799TGCTTATAACTTTTATC 3-8-2-1-3 TGCttataactTTTATC 799_2 -19.26 30693 799TGCTTATAACTTTTATC 2-10-5 TGcttataacttTTATC 799_3 -18.08 30693 799TGCTTATAACTTTTATC 5-8-4 TGCTTataactttTATC 799_4 -22.34 30693 799TGCTTATAACTTTTATC 3-10-4 TGCttataactttTATC 799_5 -19.90 30693 800TGCTTATAACTTTTATCT 3-9-3-1-2 TGCttataacttTTAtCT 800_1 -22.27 30692 800TGCTTATAACTTTTATCT 2-2-2-7-5 TGctTAtaactttTATCT 800_2 -22.61 30692 800TGCTTATAACTTTTATCT 3-10-1-1-3 TGCttataactttTaTCT 800_3 -21.45 30692 800TGCTTATAACTTTTATCT 1-1-1-1-2-8-4 TgCtTAtaacttttATCT 800_4 -20.79 30692800 TGCTTATAACTTTTATCT 4-1-1-10-2 TGCTtAtaacttttatCT 800_5 -20.89 30692801 CTGCTTATAACTTTTATC 2-1-1-8-2-1-3 CTgCttataactTTtATC 801_1 -20.0530693 801 CTGCTTATAACTTTTATC 4-8-1-3-2 CTGCttataactTttaTC 801_2 -21.0230693 801 CTGCTTATAACTTTTATC 2-1-1-10-4 CTgCttataactttTATC 801_3 -20.6930693 801 CTGCTTATAACTTTTATC 1-1-2-10-1-1-2 CtGCttataactttTaTC 801_4-18.86 30693 801 CTGCTTATAACTTTTATC 1-1-4-9-3 CtGCTTataacttttATC 801_5-21.47 30693 802 CTCTGCTTATAACTTTT 1-1-1-1-1-6-2-1-3 CtCtGcttataACtTTT802_1 -18.92 30696 802 CTCTGCTTATAACTTTT 1-1-1-1-1-7-2-1-2CtCtGcttataaCTtTT 802_2 -18.47 30696 802 CTCTGCTTATAACTTTT 1-1-2-8-1-1-3CtCTgcttataaCtTTT 802_3 -19.44 30696 802 CTCTGCTTATAACTTTT 1-2-2-7-1-1-3CtcTGcttataaCtTTT 802_4 -19.02 30696 802 CTCTGCTTATAACTTTT 3-1-1-10-2CTCtGcttataacttTT 802_5 -18.16 30696 803 CCTCTGCTTATAACTTT 1-1-2-7-2-1-3CcTCtgcttatAAcTTT 803_1 -20.60 30697 803 CCTCTGCTTATAACTTT 2-9-1-3-2CCtctgcttatAactTT 803_2 -19.28 30697 803 CCTCTGCTTATAACTTT 2-2-1-7-1-2-2CCtcTgcttataActTT 803_3 -20.58 30697 803 CCTCTGCTTATAACTTT 1-2-1-8-1-2-2CctCtgcttataActTT 803_4 -18.06 30697 803 CCTCTGCTTATAACTTT 2-1-1-9-1-1-2CCtCtgcttataaCtTT 803_5 -21.12 30697 804 CTACTATACTTTCCTCT 3-8-2-2-2CTActatacttTCctCT 804_1 -22.54 30709 804 CTACTATACTTTCCTCT 1-1-1-9-2-1-2CtActatactttCCtCT 804_2 -21.39 30709 804 CTACTATACTTTCCTCT 1-2-1-8-1-2-2CtaCtatactttCctCT 804_3 -19.70 30709 804 CTACTATACTTTCCTCT 2-11-1-1-2CTactatactttcCtCT 804_4 -20.45 30709 804 CTACTATACTTTCCTCT 1-3-1-8-1-1-2CtacTatactttcCtCT 804_5 -19.77 30709 805 TCTACTATACTTTCCTCT2-1-1-9-1-2-2 TCtActatactttCctCT 805_1 -21.40 30709 805TCTACTATACTTTCCTCT 2-2-1-8-1-2-2 TCtaCtatactttCctCT 805_2 -22.20 30709805 TCTACTATACTTTCCTCT 2-11-1-2-2 TCtactatactttCctCT 805_3 -21.20 30709805 TCTACTATACTTTCCTCT 2-1-1-10-1-1-2 TCtActatactttcCtCT 805_4 -21.5230709 805 TCTACTATACTTTCCTCT 2-2-1-9-1-1-2 TCtaCtatactttcCtCT 805_5-22.32 30709 806 TTCTACTATACTTTCCT 1-1-1-8-1-3-2 TtCtactatacTttcCT 806_1-18.06 30711 806 TTCTACTATACTTTCCT 1-2-1-7-1-3-2 TtcTactatacTttcCT 806_2-18.02 30711 806 TTCTACTATACTTTCCT 1-1-1-1-1-7-1-1-3 TtCtActatactTtCCT806_3 -20.41 30711 806 TTCTACTATACTTTCCT 1-1-1-10-4 TtCtactatacttTCCT806_4 -20.90 30711 806 TTCTACTATACTTTCCT 1-1-1-1-1-9-3 TtCtActatactttCCT806_5 -20.11 30711 807 TTCTACTATACTTTCCTC 1-2-1-8-1-1-1-1-2TtcTactatactTtCcTC 807_1 -19.51 30710 807 TTCTACTATACTTTCCTC1-1-1-2-1-6-1-3-2 TtCtaCtatactTtccTC 807_2 -19.77 30710 807TTCTACTATACTTTCCTC 1-1-1-1-1-9-1-1-2 TtCtActatactttCcTC 807_3 -19.4430710 807 TTCTACTATACTTTCCTC 1-1-1-12-3 TtCtactatactttcCTC 807_4 -20.0430710 807 TTCTACTATACTTTCCTC 1-2-1-1-1-10-2 TtcTaCtatactttccTC 807_5-19.43 30710 808 TTTCCATCTACTATTAAT 1-1-3-7-3-1-2 TtTCCatctactATTaAT808_1 -21.43 39804 808 TTTCCATCTACTATTAAT 2-1-2-7-1-1-1-1-2TTtCCatctactAtTaAT 808_2 -19.50 39804 808 TTTCCATCTACTATTAAT1-1-4-6-1-2-3 TtTCCAtctactAttAAT 808_3 -20.72 39804 808TTTCCATCTACTATTAAT 2-1-2-8-1-1-3 TTtCCatctactaTtAAT 808_4 -19.43 39804808 TTTCCATCTACTATTAAT 4-1-1-8-4 TTTCcAtctactatTAAT 808_5 -20.12 39804809 TTTCCATCTACTATTAA 5-6-3-1-2 TTTCCatctacTATtAA 809_1 -21.74 39805 809TTTCCATCTACTATTAA 2-1-2-6-2-1-3 TTtCCatctacTAtTAA 809_2 -20.76 39805 809TTTCCATCTACTATTAA 1-1-3-6-1-1-4 TtTCCatctacTaTTAA 809_3 -20.75 39805 809TTTCCATCTACTATTAA 2-1-2-7-5 TTtCCatctactATTAA 809_4 -20.54 39805 809TTTCCATCTACTATTAA 5-9-3 TTTCCatctactatTAA 809_5 -20.18 39805 810GTTTCCATCTACTATTA 3-9-2-1-2 GTTtccatctacTAtTA 810_1 -20.81 39806 810GTTTCCATCTACTATTA 1-1-1-1-1-7-1-1-3 GtTtCcatctacTaTTA 810_2 -19.35 39806810 GTTTCCATCTACTATTA 2-2-1-7-1-2-2 GTttCcatctacTatTA 810_3 -19.64 39806810 GTTTCCATCTACTATTA 3-1-1-8-4 GTTtCcatctactATTA 810_4 -21.37 39806 810GTTTCCATCTACTATTA 1-2-2-10-2 GttTCcatctactatTA 810_5 -18.14 39806 811AATACAAAATCATCTTAC 3-1-2-6-1-1-4 AATaCAaaatcaTcTTAC 811_1 -18.05 39836811 AATACAAAATCATCTTAC 4-9-5 AATAcaaaatcatCTTAC 811_2 -18.25 39836 811AATACAAAATCATCTTAC 3-1-2-7-5 AATaCAaaatcatCTTAC 811_3 -19.20 39836 811AATACAAAATCATCTTAC 2-1-3-7-5 AAtACAaaatcatCTTAC 811_4 -18.12 39836 811AATACAAAATCATCTTAC 1-1-4-7-5 AaTACAaaatcatCTTAC 811_5 -19.50 39836 812AATACAAAATCATCTTACA 2-2-2-6-4-1-2 AAtaCAaaatcaTCTTaCA 812_1 -20.31 39835812 AATACAAAATCATCTTACA 4-8-3-2-2 AATAcaaaatcaTCTtaCA 812_2 -19.80 39835812 AATACAAAATCATCTTACA 3-1-2-6-2-1-4 AATaCAaaatcaTCtTACA 812_3 -21.9139835 812 AATACAAAATCATCTTACA 1-1-4-7-2-2-2 AaTACAaaatcatCTtaCA 812_4-19.93 39835 812 AATACAAAATCATCTTACA 5-8-1-1-4 AATACaaaatcatCtTACA 812_5-20.93 39835 813 TAATACAAAATCATCTTA 1-1-4-6-3-1-2 TaATACaaaatcATCtTA813_1 -18.46 39837 813 TAATACAAAATCATCTTA 5-8-5 TAATAcaaaatcaTCTTA 813_2-19.57 39837 813 TAATACAAAATCATCTTA 5-9-4 TAATAcaaaatcatCTTA 813_3-18.44 39837 813 TAATACAAAATCATCTTA 2-1-3-8-4 TAaTACaaaatcatCTTA 813_4-18.20 39837 813 TAATACAAAATCATCTTA 1-1-4-8-4 TaATACaaaatcatCTTA 813_5-18.18 39837 814 TAATACAAAATCATCTTAC 2-1-3-6-4-1-2 TAaTACaaaatcATCTtAC814_1 -19.95 39836 814 TAATACAAAATCATCTTAC 4-1-1-6-3-1-3TAATaCaaaatcATCtTAC 814_2 -20.22 39836 814 TAATACAAAATCATCTTAC1-2-3-6-1-1-5 TaaTACaaaatcAtCTTAC 814_3 -19.14 39836 814TAATACAAAATCATCTTAC 5-8-2-1-3 TAATAcaaaatcaTCtTAC 814_4 -19.90 39836 814TAATACAAAATCATCTTAC 4-1-1-8-5 TAATaCaaaatcatCTTAC 814_5 -19.94 39836 815TAATACAAAATCATCTTACA 3-2-2-6-2-1-1-1-2 TAAtaCAaaatcaTCtTaCA 815_1 -20.8439835 815 TAATACAAAATCATCTTACA 2-3-1-8-2-1-3 TAataCaaaatcatCTtACA 815_2-18.77 39835 815 TAATACAAAATCATCTTACA 2-1-2-1-1-7-2-2-2TAaTAcAaaatcatCTtaCA 815_3 -19.66 39835 815 TAATACAAAATCATCTTACA1-1-1-1-2-8-1-1-4 TaAtACaaaatcatCtTACA 815_4 -19.11 39835 815TAATACAAAATCATCTTACA 4-10-1-1-1-1-2 TAATacaaaatcatCtTaCA 815_5 -19.2239835 816 TCTGTATACACCATCCCA 2-10-1-1-1-1-2 TCtgtatacaccAtCcCA 816_1-24.49 46389 816 TCTGTATACACCATCCCA 2-3-1-6-1-3-2 TCtgtAtacaccAtccCA816_2 -23.81 46389 816 TCTGTATACACCATCCCA 2-10-1-3-2 TCtgtatacaccAtccCA816_3 -23.72 46389 816 TCTGTATACACCATCCCA 2-1-1-10-1-1-2TCtGtatacaccatCcCA 816_4 -24.75 46389 816 TCTGTATACACCATCCCA2-3-1-8-1-1-2 TCtgtAtacaccatCcCA 816_5 -24.53 46389 816TCTGTATACACCATCCCA 2-3-1-10-2 TCtgtAtacaccatccCA 816_6 -23.76 46389 817TTCTGACTCCCTATCCA 1-1-1-12-2 TtCtgactccctatcCA 817_1 -22.56 46417 818TTTCTGACTCCCTATCC 1-2-1-11-2 TttCtgactccctatCC 818_1 -22.64 46418

Designs refer to the gapmer design, F-G-F′, where each number representsthe number of consecutive modified nucleosides, e.g 2′ modifiednucleosides (first number=5′ flank), followed by the number of DNAnucleosides (second number=gap region), followed by the number ofmodified nucleosides, e.g 2′ modified nucleosides (third number=3′flank), optionally preceded by or followed by further repeated regionsof DNA and LNA, which are not necessarily part of the contiguoussequence that is complementary to the target nucleic acid. For someoligonucleotides in table 3 the flanks are mixed flanks, such flanksstart and end with a 2′ modified nucleosides, in these cases the gapregion is the number above 5 not located at the 5′ or 3′ terminal in ofthe design.

For the oligonucleotide compounds capital letters represent beta-D-oxyLNA nucleosides, lowercase letters represent DNA nucleosides, all LNA Care 5-methyl cytosine, and 5-methyl DNA cytosines are presented by “e”,all internucleoside linkages are phosphorothioate internucleosidelinkages.

Oligonucleotides with an EX-EX indication as Start on SEQ ID NO: 1 areexon-exon spanning oligonucleotides designed to be complementary acrossexon-exon junctions of SNHG14-023 (ENST00000554726). Theoligonucleotides primarily span exon2 and exon3 (i.e. are complementaryto a region in exon2 and a region in exon 3)

Oligonucleotide Synthesis

Oligonucleotide synthesis is generally known in the art. Below is aprotocol which may be applied. The oligonucleotides of the presentinvention may have been produced by slightly varying methods in terms ofapparatus, support and concentrations used.

Oligonucleotides are synthesized on uridine universal supports using thephosphoramidite approach on a MerMade12 or an Oligomaker DNA/RNAsynthesizer at 1-4 μmol scale. At the end of the synthesis, theoligonucleotides are cleaved from the solid support using aqueousammonia for 5-16 hours at 60° C. The oligonucleotides are purified byreverse phase HPLC (RP-HPLC) or by solid phase extractions andcharacterized by UPLC, and the molecular mass is further confirmed byESI-MS.

Elongation of the Oligonucleotide:

The coupling of β-cyanoethyl-phosphoramidites (DNA-A(Bz), DNA-G(ibu),DNA-C(Bz), DNA-T, LNA-5-methyl-C(Bz), LNA-A(Bz), LNA-G(dmf), LNA-T oramino-C6 linker) is performed by using a solution of 0.1 M of the5′-O-DMT-protected amidite in acetonitrile and DCI(4,5-dicyanoimidazole) in acetonitrile (0.25 M) as activator. For thefinal cycle a phosphoramidite with desired modifications can be used,e.g. a C6 linker for attaching a conjugate group or a conjugate group assuch. Thiolation for introduction of phosphorthioate linkages is carriedout by using xanthane hydride (0.01 M in acetonitrile/pyridine 9:1).Phosphordiester linkages can be introduced using 0.02 M iodine inTHF/Pyridine/water 7:2:1. The rest of the reagents are the onestypically used for oligonucleotide synthesis.

Purification by RP-HPLC:

The crude compounds are purified by preparative RP-HPLC on a PhenomenexJupiter C18 10μ 150×10 mm column. 0.1 M ammonium acetate pH 8 andacetonitrile is used as buffers at a flow rate of 5 mL/min. Thecollected fractions are lyophilized to give the purified compoundtypically as a white solid.

Abbreviations

DCI: 4,5-Dicyanoimidazole

DCM: Dichloromethane

DMF: Dimethylformamide

DMT: 4,4′-Dimethoxytrityl

THF: Tetrahydrofurane

Bz: Benzoyl

Ibu: Isobutyryl

RP-HPLC: Reverse phase high performance liquid chromatography

T_(m) Assay

Oligonucleotide and RNA target duplexes are diluted to 3 mM in 500 mlRNase-free water and mixed with 500 ml 2×T_(m)-buffer (200 mM NaCl, 0.2mM EDTA, 20 mM Naphosphate, pH 7.0). The solution is heated to 95° C.for 3 min and then allowed to anneal in room temperature for 30 min. Theduplex melting temperatures (T_(m)) is measured on a Lambda 40 UV/VISSpectrophotometer equipped with a Peltier temperature programmer PTP6using PE Templab software (Perkin Elmer). The temperature is ramped upfrom 20° C. to 95° C. and then down to 25° C., recording absorption at260 nm. First derivative and the local maximums of both the melting andannealing are used to assess the duplex T_(m).

Preparation of Mouse Primary Cortical Neuron Cell Cultures

Primary cortical neuron cultures were prepared from mouse embryo brainsof 15 days of age according to standard procedure. In brief, cultureplates were coated with Poly-L-Lysine (50 μg/ml Poly-L-Lysine, 10 mMNa-tetraborate, pH 8 buffer) for 2-3 hrs at room temperature. The plateswere washed with 1×PBS before use. Harvested mouse embryo brains weredissected and homogenized by a razor blade and submerged into 38 mldissection medium (HBSS, 0.01 M Hepes, Penicillin/Streptomycin). Then, 2ml trypsin was added and cells were incubated for 30 min at 37° C. andcentrifuged down. The cells were dissolved in 20 ml DMEM (+10% FBS) andpassed through a syringe for further homogenization. This was followedby centrifugation at 500 rpm for 15 mins. The cells were dissolved inDMEM (+10% FBS) and seeded in 96 well plates (0.1× 10{circumflex over( )}6 cells/well in 100 μl). The neuronal cell cultures were ready foruse directly after seeding.

Screening Oligonucleotides in Mouse Primary Cortical Neuron CellCultures

Cells were cultured in growth medium (Gibco Neurobasal medium, B27supplement, Glutamax, Pencillin-streptomycin) in 96-well plates andincubated with oligonucleotides for 3 days at the desiredconcentrations. Total RNA was isolated from the cells and the knock-downefficacy was measured by qPCR analysis using the qScript™ XLT One-StepRT-qPCR ToughMix®, Low ROX™ kit from Quanta Bioscience (95134-500). Acommercial taqman assays from Thermo Fisher Scientific was used tomeasure Ube3a_ATS including GAPDH for normalization.

Generation of Human Primary Neuronal Cell Cultures

Any cell lines at any described time point was incubated at 37° C., 5%CO2 concentration and 95% relative humidity.

Human Induced Pluripotent Stem Cells (hiPSC) Culture

Whole human blood samples were obtained from patients diagnosed withAngelman syndrome. The subsequent cultures of primary Peripheral BloodMononuclear Cells (PMCSs) were enriched for erythroblasts.Patient-specific iPSC lines were generated by reprogramming erythroblastwith CytoTune-iPS Sendai Reprogramming Kit (Thermo Fisher Scientific).Derived iPSC lines were maintained in feeder-free conditions usinghESC-qualified Matrigel (Corning) in mTESR1 (STEMCELL Technologies) withdaily medium replacement. Upon reaching confluence, colonies weredissociated into cell cluster of 50-200 μm in size using Gentle CellDissociation Reagent (STEMCELL Technologies) and subcultured at a ratioof 1:10-1:20 in the presence of 10 μM Y-27632 (Calbiochem).

Differentiation into Neural Progenitor Cells (NPC)

Upon induction of neural differentiation iPSC-derived cells weremaintained in basal medium composed of equal volumes of DMEM:F12Glutamax medium and Neurobasal medium (Gibco, Invitrogen), supplementedwith 1×B27 (Gibco, Invitrogen), 1×N2 (Gibco, Invitrogen), 0.1 mMbeta-mercaptoethanol (Gibco, Invitrogen) and indicated supplements.

Neural progenitor cells (NPCs) were derived from hiPSCs by dual SMADinhibition and according to published procedures with slightmodifications (Chambers et al. 2009 Nat Biotechnol. Vol. 3 pp. 275-80,Boissart et al., 2013 Transl Psychiatry. 3:e294). HiPSCs weredissociated with Accutase (Innovative Cell Technologies Inc.) into asingle cell suspension and resuspended in basic medium furthersupplemented with 10 μM Y-27632 (Calbiochem), 5 ng/ml FGF (Peprotech),10 μM SB-431542 (Calbiochem) and 100 nM LDN (Calbiochem). Single cellsuspension was transferred to AggreWell800 plates (STEMCELLTechnologies) enabling the formation of aggregates consisting of 8000cells. After 5 days neural aggregates were transferred onto platescoated with poly-L-ornithine (Sigma) and laminin (Roche) and allowed toform neural rosettes under continued dual SMAD inhibition (SB-431542 andLDN) in basic medium supplemented with FGF. Neural rosettes wereselectively isolated using STEMdiff™ Neural Rosette Selection Reagent(STEMCELL Technologies), replated onto dishes coated withpoly-L-ornithine and Laminin521 (BioLamina) and expanded in basic mediumsupplemented with 10 ng/ml FGF (Peprotech), 10 ng/ml EGF (RnD), and 20ng/ml BDNF (Peprotech). When reaching confluency, cells wereenzymatically dissociated with 0.05% Trypsin/EDTA (Gibco, Invitrogen)and sub-cultured. Continued passaging in basic medium supplemented withFGF, EGF and BDNF leads to a stable neural progenitor cell line (NPCline) within 10 to 20 passages. A stable neural progenitor cell line isdefined by its capacity to self-renew and by the expression of thedevelopmental stage-specific markers Sox2 and Nestin. Upon specificstimuli, NPCs differentiate into neuronal (MAP2+, Tau+, HuC/D+) andastroglial (GFAP+) progenies (Dunkley et al., 2015 Proteomics Clin Appl.Vol. 7-8 pp. 684-94).

NPC Culture

Conditions for NPC culture have been described previously and were usedwith slight modifications (Boissart et al., 2013 Transl Psychiatry.3:e294). In brief, cells were maintained in dishes coated withLaminin521 (BioLamina) and cultured in basic medium [composed of equalvolumes of DMEM:F12 Glutamax medium and Neurobasal medium (Gibco,Invitrogen), supplemented with 1×B27 (Gibco, Invitrogen), 1×N2 (Gibco,Invitrogen), 0.1 mM beta-mercaptoethanol (Gibco, Invitrogen)] andsupplemented with 10 ng/ml FGF (Peprotech), 10 ng/ml EGF (RnD), and 20ng/ml BDNF (Peprotech).

Differentiation into Neuronal Cell Culture

To induce neuronal differentiation of NPC, cells were dissociated with0.05% Trypsin/EDTA (Gibco, Invitrogen) into single cell suspension andseeded onto Laminin521 (BioLamina) coated dishes at a density of 12.000cells/cm2 and maintained in basic medium supplemented with 200 ng/ml Shh(Peprotech), 100 ng/ml FGF8 (Peprotech), and 100 μM ascorbic acidphosphate (Sigma) for a period of 7 days. Subsequently, cells werereplated in basal medium supplemented with 20 ng/ml BDNF (Peprotech), 10ng/ml GDNF (Peprotech), 0.5 mM cAMP (BIOLOG Life Science), and 100 μMascorbic acid phosphate (Sigma) at a density of 45000 cells/cm2 anddifferentiated for a period of 21 days. At day 21 of differentiation,differentiated neuronal cultures were replated onto thescreening-compatible plate format. Replating was performed bydissociating the cultures with Accutase (Innovative Cell TechnologiesInc.) into a single cell suspension. Cells were seeded at a density of200.000 cells/cm2 in presence of 10 μM Y-27632 (a cell-permeable,reversible, inhibitor of Rho kinases from Calbiochem) into the 384 wellmicrotiter plates for final oligonucleotides screening assay. Neuronalcultures were further differentiated for additional 7 days in basalmedium supplemented with 20 ng/ml BDNF (Peprotech), 10 ng/ml GDNF(Peprotech), 0.5 mM cAMP (BIOLOG Life Science), and 100 μM ascorbic acidphosphate (Sigma). Differentiation medium was exchanged twice per week.After a total differentiation period of 35 days neuronal cell cultureswere ready for oligonucleotide treatment.

Screening Oligonucleotides in Human Neuronal Cell Cultures—384 WellSystem

For screening, oligonucleotide stocks were pre-diluted to the indicatedconcentrations with water into 384 well microtiter plates (compoundplate). The plate layout served as a treatment template. Two microliteroligonucleotide dilution from each well was transferred from thecompound plate to a respective culture plate. All liquid handling wasdone under sterile conditions in a laminar flow using a semi-automatedlaboratory robotic system (Beckmancoulter). Neuronal cell cultures wereincubated with oligonucleotides for 5 days without media change.Subsequently, neuronal cultures were lysed and processed for qPCR assaywith RealTime ready Cell lysis and RNA Virus Master kit (Roche). Liquidhandling was performed using a semi-automated laboratory robotic system(Beckmancoulter). Samples were analyzed by a Lightcycler480 real-timePCR system (Roche).

Activity of the oligonucleotides was assessed by qPCR monitoringtranscript abundance of UBE3A using the following primers and probes

UBE3a-Sense: Forward primer: (SEQ ID NO: 837) ATATGTGGAAGCCGGAATCT,Reverse primer: (SEQ ID NO: 838) TCCCAGAACTCCCTAATCAGAA,Internal probe labeled with dye FAM: (SEQ ID NO: 839)ATGACGGTGGCTATACCAGG

The RT-qPCR was multiplexed with PPIA (peptidylprolyl isomerase A) ashousekeeping gene for normalization. PPIA primers and probe labeled withthe dye VIC were purchased from Thermo Fisher Scientific (assay IDHs99999904_m1). Each plate includes a non-targeting oligonucleotide(mock) as negative control (TTGaataagtggaTGT (SEQ ID NO: 846)) and areference oligonucleotide CMP ID NO: 41_1, resulting in up-regulation ofUBE3A mRNA.

Selectivity of oligonucleotides was verified by counter screening forSNORD115 transcript, which is located upstream of SNORD109B onchromosome 15. Expression of SNORD115 was monitored by qPCR using thefollowing primers and probe

Forward primer: (SEQ ID NO: 840) GGGTCAATGATGAGAACCTTAT, Reverse primer(SEQ ID NO: 841) GGGCCTCAGCGTAATCCTATT,Internal probe labeled with the dye FAM: (SEQ ID NO: 842)TTCTGAAGAGAGGTGATGACTTAAAA

The RT-qPCR was multiplexed with PPIA (Thermo Fisher Scientific) uponoligonucleotide treatment.

The reduction of the SNHG14 transcript downstream of SNORD109B (alsotermed the UBE3A suppressor) was measured by RT-qPCR using the followingprimers and probe

Forward primer: (SEQ ID NO: 843) ATCCGAGGCATGAATCTCAC, Reverse primer:(SEQ ID NO: 844) CAGGCCAAAACCCTTGATAA,Internal probe labeled with dye FAM: (SEQ ID NO: 845)TTGCTGAGCATTTTTGCATC

The RT-qPCR was multiplexed with PPIA (Thermo Fisher Scientific).

Data are presented as average % expression relative to mock across allplates and normalized to the reference oligonucleotide to account forplate to plate variation.

Screening Oligonucleotides in Human Neuronal Cell Cultures—96 WellSystem

For screening, oligonucleotide stocks were pre-diluted to the indicatedconcentrations with water into 96 well microtiter plates (compoundplate). The plate layout served as a treatment template. Two microliteroligonucleotide dilution from each well was transferred from thecompound plate to a respective culture plate. All liquid handling wasdone under sterile conditions in a laminar flow using a semi-automatedlaboratory robotic system (Beckman Coulter). Neuronal cell cultures wereincubated with oligonucleotides for 5 days without media change.Subsequently, neuronal cultures were lysed and RNA purified using RNApurification kit Pure Link Pro96 (12173011A) LifeTechnologies. Liquidhandling was performed using a semi-automated laboratory robotic system(Beckmancoulter). qPCR analysis of Ube3a and Ube3a-ATS was carried outon a ViiA™ 7 Real-Time PCR System Thermo Fisher Scientific using theqScript™ XLT 1-Step RT-qPCR ToughMix Low ROX, from Quanta (95134-50).

The following primers and probes were used:

qPCR UBE3a-Sense: Forward primer: (SEQ ID NO: 697) ATATGTGGAAGCCGGAATCT,Reverse primer: (SEQ ID NO: 698) TCCCAGAACTCCCTAATCAGAA,Internal probe labeled with dye FAM: (SEQ ID NO: 699)ATGACGGTGGCTATACCAGGqPCR SNHG14 transcript downstream of SNORD109B (also termed the UBE3Asuppressor): Commercially available primer and probe set fromThermoFisher: Hs01372957_m1. These primers amplifies a 87 bp exon-exonspanning sequence in the Genbank transcript AF400500.1QPCR GAPDH Transcript:

Commercially available primer and probe set from Thermofisher: GeneSymbol: with following assay details: RefSeq: NM_002046.3, Probe ExonLocation:3, Amplicon Size: 122 bp. Corresponding TaqMan Assay ID:Hs99999905_m1.

The RT-qPCR for both Ube3a and Ube3a-ATS was multiplexed with GAPDH ashousekeeping gene for normalization. Each plate includes a non-targetingoligonucleotide (mock) as negative control (TTGaataagtggaTGT (SEQ ID NO:846)) and a reference oligonucleotide CMP ID NO: 21_1, resulting inup-regulation of UBE3A mRNA. Moreover panel of oligos not targeting Ub3aor SNHG14 transcript downstream of SNORD109B (also termed the UBE3Asuppressor) were included to monitor the assay noise and risk ofdetecting false positives. These were randomly distributed over theplates.

Control Oligonucleotides:

(SEQ ID NO: 819) CGAaccactgaaCAA (SEQ ID NO: 820) CGAaccactgaacAAA(SEQ ID NO: 821) CGAagtgcacaCG (SEQ ID NO: 822) GCGtaaagagaGGT(SEQ ID NO: 823) GAGAaggcacagaCGG (SEQ ID NO: 824) GCGaagtgcacaCGG(SEQ ID NO: 825) GAGaaggcacagaCGG (SEQ ID NO: 826) CGAaccactgAACA(SEQ ID NO: 827) GAAccactgaacAAA (SEQ ID NO: 828) caGCGtaaagagaGG(SEQ ID NO: 829) GCgtaaagagAGG (SEQ ID NO: 830) CGAaccactgaAC(SEQ ID NO: 831) CGAAccactgaaCAAA (SEQ ID NO: 832) AGCgaagtgcacaCGG(SEQ ID NO: 833) AGGtgaagcgaAGTG (SEQ ID NO: 834) TAGTaaactgagCCA(SEQ ID NO: 835) AGAaggcacagaCGG (SEQ ID NO: 836) CCGcagtatggaTCG

Example 1—Oligonucleotide Activity in Mouse Primary Neuronal CellCultures

Oligonucleotides targeting the part of SNHG14 long non-coding RNA whichis antisense to the UBE3A pre-mRNA (position 55319 to 141053 of SEQ IDNO: 1) were tested for their ability to reduce the SNHG14 longnon-coding RNA transcript preventing UBE3A expression (also termed UBE3Asuppressor or UBE3A-SUP in the data table) and their ability to induceUBE3A mRNA re-expression in mouse primary cortical neuron cell cultures,obtained as described in the “Materials and methods” section above. Theoligonucleotide concentration was 5 microM.

The oligonucleotides were screened according to the protocol forscreening in mouse cortical neuron cell cultures described in thesection “Materials and methods”. The results are shown in table 4.

TABLE 4 Oligonucleotide activity in primarymouse neuronal cell cultures. CMP % of Mock % of Mock ID NOoligonucleotide UBE3A_SUP sd UBE3A sd 95_1 CTCAtacttgctttaAT 3.6 0.1154.1 15.1 95_2 CTcatacttgctttaAT 15.9 2.6 119.8 12.4 96_1ACatctcatacttGCTT 4.0 0.5 149.9 11.5 96_2 ACatctcatacttgcTT 9.3 3.9139.9 36.4 96_3 ACatctcatacttgCTT 3.1 0.2 143.2 3.9 97_1ACatctcatactTGCT 4.0 1.5 154.5 10.0 97_2 ACatctcatacttgCT 6.1 1.7 141.114.1 97_3 ACatctcatacttGCT 3.7 0.6 162.7 15.0 97_4 ACATctcatacttgCT 5.20.4 156.7 24.4 98_1 TAcatctcatactTGCT 5.0 0.9 159.0 15.6 98_2TAcatctcatacttgCT 15.5 5.3 130.4 3.4 98_3 TACAtctcatacttgCT 4.7 0.4140.3 38.2 101_1 TACatctcatactTGC 2.6 0.5 152.6 10.2 101_2TAcatctcatacttGC 19.2 6.0 112.0 15.0 101_3 TAcatctcatactTGC 3.5 0.4117.2 13.7 101_4 TACAtctcatacttGC 3.0 0.7 140.5 12.4 100_1CTAcatctcatactTGC 5.4 0.8 160.4 4.1 100_2 CTacatctcatacttGC 9.6 3.7159.2 14.5 100_3 CTacatctcatactTGC 3.0 0.1 133.2 5.9 99_2CCtacatctcatacttGC 7.8 1.4 150.7 11.0 99_3 CCtacatctcatactTGC 3.2 0.6134.7 12.5 99_4 CCtacatctcatacTTGC 2.7 0.2 145.2 4.7 102_1CCTAcatctcatactTG 5.8 1.7 127.0 24.5 102_2 CCtacatctcatactTG 20.2 6.6129.7 9.2 102_4 CCTacatctcatacTTG 4.0 0.6 140.2 7.2 102_3CCTacatctcatactTG 3.9 1.0 133.3 10.0 104_1 CCTacatctcataCTT 6.6 1.5136.5 8.7 104_3 CCtacatctcatACTT 3.5 0.4 131.4 6.0 103_1ACCtacatctcataCTT 5.8 1.4 130.8 0.7 103_2 ACctacatctcatacTT 11.4 2.2123.6 12.4 103_3 ACctacatctcatACTT 5.8 0.8 132.2 4.5 105_1TACCtacatctcatacTT 5.2 0.8 152.3 7.2 106_1 TTAcctacatctcataCTT 13.3 3.0140.1 17.5 106_2 TTacctacatctcatacTT 21.0 1.4 116.9 15.0 107_1ACCTacatctcataCT 6.2 0.9 119.2 3.4 107_2 ACctacatctcataCT 14.3 7.4 142.913.7 108_1 TACCtacatctcataCT 5.6 1.0 127.0 10.7 108_2 TAcctacatctcataCT21.4 12.5 117.1 8.5 109_1 TTacctacatctcaTACT 4.4 0.4 138.9 1.2 109_2TTacctacatctcataCT 22.9 3.3 117.1 13.0 110_1 TTAcctacatctcaTAC 8.7 2.1133.2 5.1 110_2 TTacctacatctcatAC 21.0 5.1 111.4 11.1 111_1GTtacctacatctCATA 8.0 2.4 143.8 14.8 111_2 GTtacctacatctcaTA 19.0 2.3115.4 4.1 112_1 GTTacctacatctCAT 6.6 1.4 145.5 16.8 112_2GTtacctacatctcAT 15.8 4.5 120.3 8.1 126_1 TCACtttccagatatCA 8.0 1.9133.8 5.4 126_3 TCactttccagatatCA 53.4 75.9 112.0 11.4 128_1ACATgtccctttataTT 16.3 2.5 114.7 11.1 128_2 ACatgtccctttataTT 14.8 1.1136.9 6.2 129_1 ACAtgtccctttaTAT 11.8 1.9 135.0 14.3 132_1CTCAtccctccaagaAA 9.1 1.6 131.7 8.4 132_2 CTcatccctccaagaAA 11.2 3.9159.3 17.7

Example 2—Oligonucleotide Activity in Human Neuronal Cell Cultures

Oligonucleotides targeting human SNHG14 in the region downstream ofSNORD109B corresponding to position 25278410 to 25419462 on chromosome15 (SEQ ID NO: 1) were tested in patient derived human neuronal cellcultures (see protocol in “Materials and methods” section). Theoligonucleotides ability to reduce the SNHG14 transcript in the regiondownstream of SNORD109B (also termed UBE3A suppressor or UBE3A-SUP inthe data table), without affecting expression of SNORD115 was analyzed.Furthermore, the ability to induce UBE3A mRNA re-expression wasanalyzed.

The oligonucleotides were screened according to the protocol forscreening oligonucleotides in human neuronal cell cultures described inthe section “Materials and methods” above.

The results are shown in table 5. The expression of UBE3A mRNA has beenmeasured for all compounds, whereas the knock-down of the UBE3Asuppressor and the maintenance of SNORD1115 levels have not beenanalyzed for all compounds.

TABLE 5 Oligonucleotide activity in patient derived human neuronal cellcultures. Start % of Mock % of Mock % of Mock SEQ ID CMP Oligo concOligo conc Oligo conc NO 1 ID NO Target 0.2 μM sd 1.0 μM sd 5.0 μM sd1678 10_1 UBE3A 107 14 88 10 151 8 1679 12_2 UBE3A 100 9 87 14 158 161687 20_1 UBE3A 87 7 102 22 213 44 1712 21_1 UBE3A 127 23 166 6 178 131712 21_1 UBE3A-SUP 81 3 82 8 72 12 1712 21_1 SNORD115 115 6 142 24 16926 4167 22_1 UBE3A 87 5 90 8 146 20 4170 27_1 UBE3A 94 16 106 11 170 104171 29_2 UBE3A 86 13 100 12 194 35 4172 30_1 UBE3A 96 6 121 12 209 279210 35_1 UBE3A 88 5 112 23 195 27 10838 37_1 UBE3A 77 7 85 9 169 2415565 38_2 UBE3A 93 11 108 6 167 34 22209 42_1 UBE3A 125 16 143 14 18017 22209 42_1 UBE3A-SUP 108 14 98 15 85 18 22209 42_1 SNORD115 101 14 9325 127 21 30449 43_1 UBE3A 99 5 95 13 115 8 30451 44_1 UBE3A 99 15 80 20141 17 30451 44_2 UBE3A 98 31 104 16 119 7 30697 46_1 UBE3A 91 8 87 5167 20 36066 49_1 UBE3A 95 6 111 10 155 29 36066 49_1 UBE3A-SUP 76 7 8424 110 31 36066 49_1 SNORD115 99 14 111 20 94 6 36068 50_1 UBE3A 109 15105 11 92 14 36068 50_1 UBE3A-SUP 122 24 93 28 73 7 36068 50_1 SNORD115120 15 113 12 99 6 37206 51_1 UBE3A 114 16 101 7 101 3 37206 51_1UBE3A-SUP 128 21 67 9 84 13 37206 51_1 SNORD115 140 26 110 9 100 1146130 52_1 UBE3A 139 3 160 1 236 36 46130 52_1 UBE3A-SUP 135 16 133 26160 32 46130 52_1 SNORD115 104 8 119 14 100 8 48145 59_1 UBE3A 179 3 12217 115 NA 48170 76_1 UBE3A 85 16 100 8 155 12 48171 80_1 UBE3A 120 7 11410 172 20 48171 78_1 UBE3A 136 31 103 20 169 11 48172 82_2 UBE3A 96 11121 4 186 32 48172 84_1 UBE3A 95 14 100 8 158 14 49343 85_1 UBE3A 97 22121 10 189 17 49722 87_1 UBE3A 111 9 126 11 177 22 52417 92_1 UBE3A 1337 140 30 140 8 52417 92_1 UBE3A-SUP 88 14 80 14 82 8 52417 92_1 SNORD115102 8 114 20 91 9 52420 93_1 UBE3A 111 14 120 9 126 16 52420 93_1UBE3A-SUP 104 23 82 20 79 8 52420 93_1 SNORD115 110 11 114 17 95 7 5395394_1 UBE3A 117 12 147 15 166 15 53953 94_1 UBE3A-SUP 92 18 81 5 86 2253953 94_1 SNORD115 124 33 122 17 106 14 60819 95_1 UBE3A 103 11 131 14175 7 60819 95_1 UBE3A-SUP 93 13 87 3 74 6 60819 95_1 SNORD115 162 19158 20 201 11 60819 95_2 UBE3A 147 10 129 20 117 2 60819 95_2 UBE3A-SUP118 24 87 13 83 8 60819 95_2 SNORD115 104 17 118 10 129 6 60823 96_1UBE3A 115 16 135 19 174 17 60823 96_1 UBE3A-SUP 104 25 93 32 91 11 6082396_2 UBE3A 108 7 114 9 115 13 60823 96_2 UBE3A-SUP 99 17 92 19 93 1060824 97_1 UBE3A 111 12 134 23 169 14 60824 97_1 UBE3A-SUP 110 27 105 3392 10 60824 97_2 UBE3A 124 13 126 12 124 11 60824 97_2 UBE3A-SUP 113 17107 33 96 20 60824 98_1 UBE3A 111 16 119 11 138 14 60824 98_1 UBE3A-SUP118 34 98 23 82 19 60824 98_1 SNORD115 109 11 123 18 114 16 60824 98_2UBE3A 128 10 109 7 136 12 60824 98_2 UBE3A-SUP 91 15 77 11 110 16 6082498_2 SNORD115 101 3 110 7 124 11 60825 99_1 UBE3A 125 6 115 5 131 1060825 99_1 UBE3A-SUP 139 18 121 34 127 45 60825 99_1 SNORD115 110 18 11212 99 19 60825 99_2 UBE3A 120 21 111 11 135 22 60825 99_2 UBE3A-SUP 9621 79 15 75 11 60825 99_2 SNORD115 104 34 113 22 131 24 60825 100_1UBE3A 123 34 139 34 145 21 60825 100_1 UBE3A-SUP 104 37 127 46 99 1760825 100_2 UBE3A 124 46 138 37 145 31 60825 100_2 UBE3A-SUP 111 36 12047 92 11 60825 101_1 UBE3A 112 18 123 15 150 13 60825 101_1 UBE3A-SUP 9618 102 14 88 12 60825 101_2 UBE3A 118 15 138 24 139 32 60825 101_2UBE3A-SUP 100 29 110 39 92 10 60826 102_1 UBE3A 132 17 120 7 125 9 60826102_1 UBE3A-SUP 113 16 83 5 88 18 60826 102_1 SNORD115 121 36 131 23 1009 60826 102_2 UBE3A 90 6 116 23 103 7 60826 102_2 UBE3A-SUP 91 7 90 1264 18 60826 102_2 SNORD115 116 15 146 27 183 28 60827 103_1 UBE3A 106 8112 10 115 9 60827 103_1 UBE3A-SUP 99 15 110 28 94 8 60827 103_2 UBE3A107 14 120 13 112 14 60827 103_2 UBE3A-SUP 97 14 118 38 93 20 60827104_1 UBE3A 128 14 111 9 111 6 60827 104_1 UBE3A-SUP 111 12 97 9 87 1960827 104_1 SNORD115 114 10 110 12 109 13 60827 104_2 UBE3A 108 10 11116 109 10 60827 104_2 UBE3A-SUP 103 13 103 33 89 9 60827 105_1 UBE3A 12213 121 12 121 4 60827 105_1 UBE3A-SUP 119 7 97 15 93 7 60827 105_1SNORD115 114 21 128 12 118 9 60827 105_2 UBE3A 123 5 110 9 114 8 60827105_2 UBE3A-SUP 110 11 89 17 94 21 60827 105_2 SNORD115 102 15 108 16107 18 60827 106_1 UBE3A 114 17 133 23 125 9 60827 106_1 UBE3A-SUP 11235 103 15 87 12 60827 106_2 UBE3A 110 12 130 22 123 14 60827 106_2UBE3A-SUP 105 19 107 27 93 10 60828 107_1 UBE3A 83 11 117 13 112 6 60828107_1 UBE3A-SUP 86 11 114 16 67 7 60828 107_1 SNORD115 108 17 130 21 13724 60828 107_2 UBE3A 143 42 117 10 122 11 60828 107_2 UBE3A-SUP 116 1292 4 100 8 60828 107_2 SNORD115 108 4 127 16 108 14 60828 108_1 UBE3A120 7 127 31 132 31 60828 108_1 UBE3A-SUP 153 33 118 34 89 17 60828108_1 SNORD115 114 9 114 9 105 15 60828 108_2 UBE3A 122 18 133 26 128 960828 108_2 UBE3A-SUP 101 19 100 28 89 17 60828 109_1 UBE3A 108 10 12914 128 5 60828 109_1 UBE3A-SUP 106 21 107 24 84 8 60828 109_2 UBE3A 10911 110 8 111 13 60828 109_2 UBE3A-SUP 95 15 86 14 83 9 60829 110_1 UBE3A104 6 83 3 101 15 60829 110_1 UBE3A-SUP 100 13 95 12 79 4 60829 110_1SNORD115 126 21 125 6 182 13 60829 110_2 UBE3A 92 7 87 8 96 7 60829110_2 UBE3A-SUP 99 7 108 9 81 5 60829 110_2 SNORD115 118 15 139 22 19839 60830 111_1 UBE3A 110 6 122 13 124 10 60830 111_1 UBE3A-SUP 104 14 9028 79 11 60830 111_2 UBE3A 115 10 120 15 121 10 60830 111_2 UBE3A-SUP114 20 89 19 87 9 60831 112_1 UBE3A 93 8 94 13 106 10 60831 112_1UBE3A-SUP 97 1 68 29 82 7 60831 112_1 SNORD115 116 20 110 13 158 2060831 112_2 UBE3A 83 8 78 7 83 6 60831 112_2 UBE3A-SUP 106 35 80 23 69 960831 112_2 SNORD115 107 6 106 8 159 21 62198 113_1 UBE3A 110 3 122 6134 9 62198 113_1 UBE3A-SUP 113 20 85 19 79 24 62198 113_1 SNORD115 11618 123 9 91 9 62284 115_1 UBE3A 105 14 98 19 141 36 62422 116_1 UBE3A130 19 142 29 172 18 62423 117_1 UBE3A 76 8 93 13 171 17 62439 118_1UBE3A 75 7 88 9 150 19 66378 119_1 UBE3A 96 14 93 5 110 10 77565 126_1UBE3A 94 6 113 5 125 14 77565 126_1 UBE3A-SUP 83 17 95 33 85 5 77565126_1 SNORD115 105 11 123 19 152 15 77565 126_2 UBE3A 95 5 126 9 111 277565 126_2 UBE3A-SUP 77 27 106 21 83 15 77565 126_2 SNORD115 115 17 15713 180 15 92321 128_1 UBE3A 102 7 91 5 111 13 92321 128_1 UBE3A-SUP 1153 104 25 91 13 92321 128_1 SNORD115 135 9 132 12 196 35 92321 128_2UBE3A 91 5 96 8 104 8 92321 128_2 UBE3A-SUP 112 20 92 20 79 7 92321128_2 SNORD115 125 7 111 13 169 12 92322 129_1 UBE3A 101 5 103 2 110 792322 129_1 UBE3A-SUP 99 39 113 12 94 13 92322 129_1 SNORD115 124 25 1146 140 13 92322 129_2 UBE3A 93 2 100 4 113 16 92322 129_2 UBE3A-SUP 109 4102 22 85 7 92322 129_2 SNORD115 103 11 99 9 152 31 97154 132_1 UBE3A100 10 128 13 142 13 97154 132_1 UBE3A-SUP 103 9 115 8 109 6 97154 132_1SNORD115 49 7 90 12 143 25 97154 132_2 UBE3A 111 8 128 17 128 17 97154132_2 UBE3A-SUP 95 7 116 9 105 13 97154 133_2 SNORD115 86 7 106 9 121 997154 133_1 UBE3A 101 3 107 11 124 19 97154 133_1 UBE3A-SUP 112 9 117 7146 25 97154 133_1 SNORD115 60 7 110 15 141 15 97154 133_2 UBE3A 94 13116 14 138 12 97154 133_2 UBE3A-SUP 116 6 128 13 148 38 97154 132_2SNORD115 70 5 108 9 160 34 106137 137_1 UBE3A 83 12 74 11 124 20 109404138_1 UBE3A 80 20 92 7 120 21 110766 139_1 UBE3A 76 5 85 12 121 17114826 140_1 UBE3A 87 10 88 11 136 9 118637 143_1 UBE3A 83 7 104 30 14128 118639 144_1 UBE3A 74 17 31 39 106 33 124160 145_2 UBE3A 89 6 95 10115 25 125499 146_1 UBE3A 83 13 76 7 124 16 125499 146_2 UBE3A 123 30 7914 102 23 125538 150_2 UBE3A 82 17 82 7 119 24

Of the 187 compounds tested approximately 90% showed re-expression ofUBE3A when compared to the mock oligonucleotide at the 5 micro Molarconcentration. The number of oligonucleotides capable of inducingre-expression of UBE3A is higher in the region between position 1 to55318 of SEQ ID NO: 1 (non-overlapping region) then in the regioncomplementary to UBE3A coding region (overlapping region. FIG. 2 plotsthe distribution of the oligonucleotides according to their position onchromosome 15 versus the UBE3A mRNA expression relative to the mockoligonucleotide.

For the oligonucleotides where SNORD115 has been tested there is nosignificant down regulation when compared to mock at 1 and 5 microM.

Example 3—Activity of Oligonucleotides Targeting the SNHG14 Transcriptin the Region Downstream of SNORD109B and Upstream of the RegionAntisense to the UBE3A Pre-mRNA

Oligonucleotides targeting position 4806-54939 of SEQ ID NO: 1 weretested in patient derived human neuronal cell cultures (see protocol in“Materials and methods” section). The oligonucleotides ability to reducethe SNHG14 transcript in the region downstream of SNORD109B (also termedUBE3A suppressor or UBE3A-SUP in the data table. Furthermore, theability to induce UBE3A mRNA re-expression was analyzed.

The oligonucleotides were screened according to the protocol forscreening oligonucleotides in human neuronal cell cultures described inthe section “Materials and methods”—“Screening oligonucleotides in humanneuronal cell cultures—96 well system”

The results are shown in table 6.

TABLE 6 Oligonucleotide activity in patient derived human neuronal cellcultures. Start SEQ CMP ID Conc % of Mock % of Mock ID NO 1 NO μMUBE3A-SUP sd UBE3A sd 4806 151_1 0.2 66 2 125 NA 4806 151_1 1 53 10 NANA 4808 152_1 0.2 49 6 167 NA 4808 152_1 1 33 4 289 NA 4809 153_1 0.2 411 208 NA 4809 153_1 1 29 10 NA NA 4811 154_1 0.2 48 3 282 NA 4811 154_11 37 5 331 NA 4812 155_1 0.2 35 5 286 64 4812 155_1 1 32 3 327 21 4972156_1 0.2 60 6 145 6 4972 156_1 1 46 14 145 NA 4973 157_1 0.2 75 9 128 64973 157_1 1 59 NA 158 NA 4979 158_1 0.2 46 9 131 NA 4979 158_1 1 37 5219 8 5058 159_1 0.2 69 6 133 19 5058 159_1 1 51 14 NA NA 5071 160_1 0.255 8 98 NA 5071 160_1 1 39 7 136 34 5078 161_1 0.2 65 7 205 18 5078161_1 1 51 10 306 31 5094 162_1 0.2 53 5 154 27 5094 162_1 1 34 8 300 655096 163_1 0.2 44 1 206 49 5096 163_1 1 36 6 316 NA 5100 164_1 0.2 34 3220 NA 5100 164_1 1 30 3 227 32 5101 165_1 0.2 38 7 245 NA 5101 165_1 136 4 246 55 5218 166_1 0.2 45 4 240 NA 5218 166_1 1 36 6 280 44 5218167_1 0.2 46 2 261 NA 5218 167_1 1 31 4 346 30 5224 168_1 0.2 39 3 37740 5224 168_1 1 33 5 338 65 5224 169_1 0.2 37 4 313 NA 5224 169_1 1 31 2308 3 5427 170_1 0.2 89 13 105 26 5427 170_1 1 117 35 124 NA 5434 171_10.2 51 5 164 10 5434 171_1 1 33 6 213 46 5785 172_1 0.2 46 5 210 NA 5785172_1 1 38 4 342 NA 5786 173_1 0.2 54 4 292 61 5786 173_1 1 39 6 552 NA6341 174_1 0.2 97 11 126 3 6341 174_1 1 90 33 NA NA 6694 175_1 0.2 44 4226 NA 6694 175_1 1 35 4 296 NA 6695 176_1 0.2 32 7 297 87 6695 176_1 129 4 263 9 6958 177_1 0.2 58 7 244 76 6958 177_1 1 47 NA NA NA 7159179_1 0.2 33 4 282 NA 7159 179_1 1 29 5 289 7 7159 178_1 0.2 43 5 248 NA7159 178_1 1 32 4 258 NA 7720 180_1 0.2 75 6 144 36 7720 180_1 1 54 7233 26 7724 181_1 0.2 72 6 177 20 7724 181_1 1 45 19 224 62 7725 182_10.2 65 5 139 37 7725 182_1 1 47 4 208 76 7725 183_1 0.2 103 13 140 27725 183_1 1 74 6 NA NA 7727 184_1 0.2 45 2 300 107 7727 184_1 1 35 2272 16 8117 185_1 0.2 87 17 122 13 8117 185_1 1 63 17 175 NA 8118 186_10.2 40 5 368 105 8118 186_1 1 33 5 NA NA 8119 187_1 0.2 62 5 197 NA 8119187_1 1 43 13 517 143 8120 188_1 0.2 96 10 136 41 8120 188_1 1 79 22 14619 8571 189_1 0.2 53 11 204 NA 8571 189_1 1 49 24 298 15 8573 190_1 0.254 9 140 9 8573 190_1 1 50 10 267 4 8574 191_1 0.2 56 1 117 NA 8574191_1 1 57 13 199 NA 8575 192_1 0.2 56 9 165 10 8575 192_1 1 54 13 246NA 8576 193_1 0.2 56 6 185 7 8576 193_1 1 52 8 330 35 8585 194_1 0.2 472 302 NA 8585 194_1 1 39 7 NA NA 8819 195_1 0.2 62 10 155 10 8819 195_11 41 3 192 7 8820 196_1 0.2 55 12 237 69 8820 196_1 1 40 3 278 26 8887197_1 0.2 69 15 301 59 8887 197_1 1 58 7 383 92 9150 198_1 0.2 49 6 NANA 9150 198_1 1 43 3 365 38 9201 199_1 0.2 79 23 88 42 9201 199_1 1 6424 140 22 9202 201_1 0.2 61 10 NA NA 9202 201_1 1 45 8 343 27 9202 200_10.2 47 3 287 76 9202 200_1 1 41 4 281 NA 9203 202_1 0.2 55 17 166 929203 202_1 1 40 5 297 54 9209 203_1 0.2 60 1 122 NA 9209 203_1 1 40 14204 8 9210 204_1 0.2 43 2 216 NA 9210 204_1 1 37 3 409 NA 9210 205_1 0.245 8 187 NA 9210 205_1 1 37 22 336 18 9211 206_1 0.2 51 10 384 17 9211206_1 1 42 3 381 35 9211 207_1 0.2 65 8 301 28 9211 207_1 1 50 5 272 539212 35_2 0.2 42 11 203 16 9212 35_2 1 44 18 335 NA 9212 208_1 0.2 64 5147 58 9212 208_1 1 50 6 260 73 9213 209_1 0.2 57 7 NA NA 9213 209_1 149 4 346 31 9214 210_1 0.2 49 7 139 NA 9214 210_1 1 45 7 223 59 10832211_1 0.2 70 6 147 10 10832 211_1 1 56 9 200 38 10837 212_1 0.2 59 9 14646 10837 212_1 1 41 6 226 47 10838 213_1 0.2 50 8 247 69 10838 213_1 144 12 307 NA 10877 214_1 0.2 108 21 115 1 10877 214_1 1 92 37 88 3211434 215_1 0.2 97 12 81 23 11434 215_1 1 80 26 111 11 11435 216_1 0.290 16 87 NA 11435 216_1 1 82 29 82 21 11436 217_1 0.2 87 6 83 11 11436217_1 1 68 26 123 NA 11438 218_1 0.2 57 5 133 NA 11438 218_1 1 44 16 188NA 11439 219_1 0.2 84 1 93 NA 11439 219_1 1 66 22 113 29 11464 220_1 0.267 9 209 51 11464 220_1 1 41 6 256 33 11507 221_1 0.2 59 6 237 NA 11507221_1 1 40 63 320 NA 11508 222_1 0.2 53 7 195 NA 11508 222_1 1 48 12 302NA 11511 223_1 0.2 41 3 210 6 11511 223_1 1 37 9 273 NA 11513 224_1 0.222 8 288 91 11513 224_1 1 26 5 360 46 11514 225_1 0.2 98 17 98 31 11514225_1 1 68 16 129 11 11736 226_1 0.2 69 8 197 80 11736 226_1 1 55 7 32966 12361 227_1 0.2 48 8 183 56 12361 227_1 1 37 4 193 46 12794 228_1 0.238 9 201 71 12794 228_1 1 32 2 362 48 12795 229_1 0.2 50 12 161 30 12795229_1 1 34 7 301 35 12796 230_1 0.2 44 12 237 86 12796 230_1 1 32 3 379106 12894 232_1 0.2 91 17 79 27 12894 232_1 1 66 10 99 24 12894 231_10.2 80 5 89 NA 12894 231_1 1 57 14 164 31 12895 234_1 0.2 88 11 75 3212895 234_1 1 68 19 91 24 12895 233_1 0.2 57 5 199 37 12895 233_1 1 38 7249 57 12896 235_1 0.2 72 3 176 9 12896 235_1 1 45 3 251 42 13223 236_10.2 40 3 267 66 13223 236_1 1 31 3 270 23 13224 238_1 0.2 33 3 265 NA13224 238_1 1 28 4 265 6 13224 237_1 0.2 38 2 212 NA 13224 237_1 1 31 1254 31 13225 239_1 0.2 42 5 317 113 13225 239_1 1 29 7 215 26 13226240_1 0.2 38 7 223 NA 13226 240_1 1 32 5 232 16 15115 241_1 0.2 61 8 37715 15115 241_1 1 41 3 377 43 15258 242_1 0.2 66 14 133 35 15258 242_1 155 10 170 17 15568 243_1 0.2 62 13 192 58 15568 243_1 1 41 11 309 515570 244_1 0.2 53 17 252 59 15570 244_1 1 44 5 332 52 15572 245_1 0.257 21 321 122 15572 245_1 1 49 7 407 77 15573 246_1 0.2 47 16 348 12915573 246_1 1 40 7 410 69 15574 247_1 0.2 48 14 326 116 15574 247_1 1 448 411 36 15722 248_1 0.2 51 3 258 17 15722 248_1 1 36 3 230 NA 16597249_1 0.2 66 19 111 39 16597 249_1 1 54 14 174 44 16603 250_1 0.2 67 2689 31 16603 250_1 1 56 6 172 32 16730 251_1 0.2 36 5 354 41 16730 251_11 31 2 326 75 16849 252_1 0.2 74 17 188 81 16849 252_1 1 48 17 282 117089 253_1 0.2 70 17 98 37 17089 253_1 1 62 19 153 13 17401 254_1 0.242 6 209 83 17401 254_1 1 29 3 327 49 24290 255_1 0.2 106 13 105 3624290 255_1 1 109 21 136 NA 24296 256_1 0.2 92 20 117 30 24296 256_1 193 15 138 21 24811 257_1 0.2 85 12 126 4 24811 257_1 1 74 12 137 1725032 258_1 0.2 50 11 329 131 25032 258_1 1 39 5 411 53 25033 259_1 0.240 10 343 50 25033 259_1 1 31 3 483 84 25250 260_1 0.2 33 10 279 4225250 260_1 1 33 4 338 65 25251 261_1 0.2 40 8 209 97 25251 261_1 1 34 3370 57 25718 262_1 0.2 56 20 113 48 25718 262_1 1 45 8 198 65 25720263_1 0.2 84 7 121 39 25720 263_1 1 72 11 88 10 25721 264_1 0.2 83 15 8740 25721 264_1 1 84 22 NA NA 26331 265_1 0.2 93 5 88 38 26331 265_1 1 818 NA NA 27165 266_1 0.2 63 3 117 39 27165 266_1 1 46 9 174 15 27248267_1 0.2 81 10 124 17 27248 267_1 1 59 10 190 112 29330 268_1 0.2 109 4124 48 29330 268_1 1 98 28 114 35 29635 269_1 0.2 45 1 218 50 29635269_1 1 33 9 267 NA 29635 270_1 0.2 55 5 225 41 29635 270_1 1 45 8 NA NA29636 271_1 0.2 48 2 285 56 29636 271_1 1 40 7 359 99 29636 272_1 0.2 483 166 5 29636 272_1 1 35 8 293 40 29637 273_1 0.2 56 5 255 47 29637273_1 1 46 4 300 105 29637 274_1 0.2 67 7 134 35 29637 274_1 1 54 7 23419 29661 275_1 0.2 51 3 167 15 29661 275_1 1 42 11 251 NA 29661 276_10.2 54 5 127 17 29661 276_1 1 39 8 229 NA 29684 277_1 0.2 40 3 168 7329684 277_1 1 31 13 NA NA 29684 278_1 0.2 46 7 179 2 29684 278_1 1 36 8NA NA 30455 279_1 0.2 102 20 96 34 30455 279_1 1 86 22 118 23 30456280_1 0.2 94 23 91 28 30456 280_1 1 83 18 134 36 30457 281_1 0.2 89 2397 37 30457 281_1 1 94 23 106 39 30458 282_1 0.2 99 14 77 27 30458 282_11 103 17 96 20 30462 283_1 0.2 66 26 98 36 30462 283_1 1 56 14 129 1330465 284_1 0.2 73 11 114 47 30465 284_1 1 57 10 197 63 30601 285_1 0.241 31 311 29 30601 285_1 1 30 16 373 40 30605 286_1 0.2 40 2 221 8630605 286_1 1 33 6 375 NA 30609 287_1 0.2 43 3 267 65 30609 287_1 1 37 5332 27 30610 288_1 0.2 46 6 253 79 30610 288_1 1 38 3 338 NA 30667 289_10.2 38 15 325 144 30667 289_1 1 36 3 461 68 30668 290_1 0.2 74 19 124 5430668 290_1 1 58 14 183 20 30669 291_1 0.2 86 18 98 40 30669 291_1 1 7812 133 26 30670 292_1 0.2 93 10 86 31 30670 292_1 1 94 16 127 22 30679293_1 0.2 85 19 83 21 30679 293_1 1 87 21 113 23 30681 294_1 0.2 92 1778 20 30681 294_1 1 100 19 86 22 30682 295_1 0.2 93 22 101 40 30682295_1 1 94 33 101 8 30699 296_1 0.2 80 24 134 6 30699 296_1 1 47 21 23236 30700 297_1 0.2 53 5 146 26 30700 297_1 1 32 8 NA NA 30700 298_1 0.247 4 221 NA 30700 298_1 1 38 0 294 NA 30701 299_1 0.2 49 4 140 NA 30701299_1 1 23 NA NA NA 30701 300_1 0.2 50 9 163 19 30701 300_1 1 39 11 34611 30702 301_1 0.2 66 9 116 36 30702 301_1 1 44 14 230 51 30711 302_10.2 41 14 288 120 30711 302_1 1 40 5 422 132 30714 303_1 0.2 45 9 355 9430714 303_1 1 31 5 355 8 30715 305_1 0.2 39 4 292 56 30715 305_1 1 34 12253 5 30715 304_1 0.2 50 13 263 87 30715 304_1 1 43 7 285 12 31630 306_10.2 92 32 134 48 31630 306_1 1 85 25 177 26 31632 307_1 0.2 94 24 92 3231632 307_1 1 86 17 109 33 31633 308_1 0.2 92 18 78 13 31633 308_1 1 10223 98 7 32755 310_1 0.2 47 12 220 40 32755 310_1 1 40 16 285 NA 32755309_1 0.2 62 6 167 NA 32755 309_1 1 40 10 225 NA 32756 311_1 0.2 55 9128 9 32756 311_1 1 56 NA 224 NA 33366 312_1 0.2 64 23 121 4 33366 312_11 56 10 137 1 33367 313_1 0.2 81 7 91 NA 33367 313_1 1 79 22 115 1233368 314_1 0.2 70 4 103 NA 33368 314_1 1 57 15 157 NA 33369 315_1 0.273 12 87 20 33369 315_1 1 67 19 155 NA 33375 316_1 0.2 79 18 100 1833375 316_1 1 51 14 159 39 33377 317_1 0.2 46 21 248 72 33377 317_1 1 419 313 NA 33378 318_1 0.2 38 17 273 63 33378 318_1 1 36 7 321 1 36606319_1 0.2 79 10 154 21 36606 319_1 1 48 9 233 65 36607 320_1 0.2 60 9157 18 36607 320_1 1 49 9 206 25 38092 321_1 0.2 51 10 221 59 38092321_1 1 41 5 328 39 38297 322_1 0.2 43 9 298 31 38297 322_1 1 34 6 36591 39173 323_1 0.2 98 8 119 27 39173 323_1 1 82 20 177 21 39174 324_10.2 89 8 139 24 39174 324_1 1 84 23 192 15 39175 325_1 0.2 93 18 167 1339175 325_1 1 68 17 203 33 39176 326_1 0.2 79 12 185 83 39176 326_1 1 5517 374 107 39228 327_1 0.2 75 12 151 29 39228 327_1 1 57 8 207 32 39230328_1 0.2 65 11 176 19 39230 328_1 1 52 19 357 NA 39231 329_1 0.2 63 19150 35 39231 329_1 1 46 6 257 43 39563 330_1 0.2 69 10 116 34 39563330_1 1 56 11 196 NA 39808 331_1 0.2 40 8 201 17 39808 331_1 1 25 5 300NA 39808 332_1 0.2 40 14 282 109 39808 332_1 1 33 7 404 81 39931 333_10.2 80 11 107 53 39931 333_1 1 70 16 112 26 41114 334_1 0.2 64 4 113 NA41114 334_1 1 28 NA 179 NA 41444 335_1 0.2 57 17 165 39 41444 335_1 1 464 290 40 41445 336_1 0.2 51 2 134 NA 41445 336_1 1 42 15 238 NA 41446337_1 0.2 63 1 108 NA 41446 337_1 1 56 14 151 22 41725 338_1 0.2 91 16130 50 41725 338_1 1 75 23 154 27 41726 339_1 0.2 66 20 142 23 41726339_1 1 55 14 193 NA 41728 340_1 0.2 60 16 137 23 41728 340_1 1 51 13233 NA 42167 341_1 0.2 70 9 138 7 42167 341_1 1 51 11 182 20 42168 343_10.2 67 9 210 92 42168 343_1 1 52 6 193 NA 42168 342_1 0.2 51 6 183 NA42168 342_1 1 46 10 275 14 42169 344_1 0.2 55 1 231 32 42169 344_1 1 353 NA NA 42169 345_1 0.2 55 7 164 41 42169 345_1 1 45 5 284 27 42287346_1 0.2 66 7 144 32 42287 346_1 1 53 5 279 34 42289 347_1 0.2 75 20125 10 42289 347_1 1 68 7 241 69 43452 348_1 0.2 62 12 231 92 43452348_1 1 48 23 257 72 43453 349_1 0.2 52 11 142 41 43453 349_1 1 44 23257 34 43562 350_1 0.2 50 13 148 35 43562 350_1 1 36 10 NA NA 43565351_1 0.2 71 10 116 43 43565 351_1 1 60 11 154 37 43566 352_1 0.2 65 19139 14 43566 352_1 1 44 8 255 23 43634 353_1 0.2 63 25 172 75 43634353_1 1 51 22 214 NA 44180 355_1 0.2 60 6 165 8 44180 355_1 1 57 25 145NA 44180 354_1 0.2 76 17 149 55 44180 354_1 1 48 10 240 29 44181 356_10.2 60 5 170 27 44181 356_1 1 43 15 154 55 44183 357_1 0.2 50 15 214 3344183 357_1 1 37 17 196 19 44184 358_1 0.2 57 5 155 31 44184 358_1 1 4710 257 94 44439 359_1 0.2 46 4 220 53 44439 359_1 1 45 2 347 52 44440360_1 0.2 48 9 261 37 44440 360_1 1 44 6 NA NA 44440 361_1 0.2 43 5 21846 44440 361_1 1 29 3 291 19 44441 362_1 0.2 50 5 192 60 44441 362_1 145 7 290 58 44441 363_1 0.2 45 10 185 51 44441 363_1 1 43 10 247 NA44442 364_1 0.2 54 8 124 24 44442 364_1 1 39 5 271 54 44442 365_1 0.2 596 166 9 44442 365_1 1 44 8 313 47 44443 367_1 0.2 55 10 161 29 44443367_1 1 40 7 314 67 44443 366_1 0.2 51 5 202 44 44443 366_1 1 41 10 30031 44477 368_1 0.2 73 6 155 58 44477 368_1 1 52 3 362 141 44478 369_10.2 82 18 130 35 44478 369_1 1 58 11 228 66 44776 370_1 0.2 60 7 128 2044776 370_1 1 46 5 274 NA 45216 371_1 0.2 50 10 149 33 45216 371_1 1 418 260 59 45217 372_1 0.2 59 7 132 45 45217 372_1 1 39 4 270 12 45217373_1 0.2 47 3 167 52 45217 373_1 1 38 4 330 62 45218 374_1 0.2 51 9 18927 45218 374_1 1 42 9 359 93 45246 375_1 0.2 61 8 175 29 45246 375_1 150 7 257 NA 45247 376_1 0.2 84 4 116 40 45247 376_1 1 74 10 144 NA 45248378_1 0.2 61 10 226 2 45248 378_1 1 50 5 367 141 45248 377_1 0.2 74 11138 29 45248 377_1 1 62 4 251 NA 45249 379_1 0.2 48 5 232 NA 45249 379_11 50 NA 312 NA 45249 380_1 0.2 54 4 203 16 45249 380_1 1 53 1 353 1245250 381_1 0.2 48 6 230 25 45250 381_1 1 40 7 387 79 45250 382_1 0.2 607 153 30 45250 382_1 1 46 3 288 43 45258 383_1 0.2 46 4 211 NA 45258383_1 1 34 6 307 29 45266 385_1 0.2 80 34 85 8 45266 385_1 1 55 13 12825 45266 384_1 0.2 92 4 128 50 45266 384_1 1 79 12 108 23 45267 386_10.2 93 23 105 13 45267 386_1 1 80 23 139 14 45268 387_1 0.2 90 17 111 145268 387_1 1 109 9 122 44 45270 388_1 0.2 97 7 146 47 45270 388_1 1 889 113 22 45271 390_1 0.2 79 12 141 14 45271 390_1 1 58 14 197 38 45271389_1 0.2 70 3 97 28 45271 389_1 1 53 6 150 26 45272 391_1 0.2 61 4 12824 45272 391_1 1 55 14 208 39 45560 392_1 0.2 86 22 97 26 45560 392_1 171 19 125 18 45627 393_1 0.2 48 14 150 64 45627 393_1 1 39 1 209 3545628 394_1 0.2 51 4 174 34 45628 394_1 1 44 8 309 30 45629 395_1 0.2 605 151 24 45629 395_1 1 48 7 297 43 45629 396_1 0.2 86 24 139 55 45629396_1 1 64 13 203 38 45635 397_1 0.2 50 10 289 61 45635 397_1 1 46 2 40156 45709 398_1 0.2 47 6 207 61 45709 398_1 1 49 6 233 NA 45709 399_1 0.256 6 206 13 45709 399_1 1 45 4 287 93 46215 400_1 0.2 78 14 122 13 46215400_1 1 60 9 114 19 46256 401_1 0.2 62 7 164 56 46256 401_1 1 45 5 21320 46257 404_1 0.2 44 4 207 44 46257 404_1 1 41 3 288 45 46257 402_1 0.248 5 197 57 46257 402_1 1 41 1 300 11 46257 403_1 0.2 51 4 265 50 46257403_1 1 44 5 382 NA 46259 405_1 0.2 46 4 NA NA 46259 405_1 1 39 10 35910 46260 406_1 0.2 52 9 153 63 46260 406_1 1 48 7 262 71 46263 407_1 0.252 9 148 9 46263 407_1 1 41 5 262 45 46264 408_1 0.2 51 17 269 72 46264408_1 1 42 8 280 55 46392 409_1 0.2 38 10 359 91 46392 409_1 1 38 8 NANA 46393 410_1 0.2 39 12 295 30 46393 410_1 1 32 12 NA NA 46420 411_10.2 75 10 69 3 46420 411_1 1 86 3 101 21 46505 412_1 0.2 65 11 97 746505 412_1 1 53 5 226 59 46505 413_1 0.2 74 16 124 19 46505 413_1 1 6913 117 11 46506 414_1 0.2 75 7 149 17 46506 414_1 1 71 10 169 118 46507415_1 0.2 86 31 119 36 46507 415_1 1 66 17 129 28 46508 416_1 0.2 86 2287 22 46508 416_1 1 67 10 142 16 47364 417_1 0.2 49 2 166 22 47364 417_11 47 13 295 NA 47365 418_1 0.2 54 3 131 29 47365 418_1 1 41 3 230 4248110 419_1 0.2 77 9 101 45 48110 419_1 1 58 8 178 68 48111 420_1 0.2 637 121 32 48111 420_1 1 51 2 238 59 48186 421_1 0.2 69 5 176 52 48186421_1 1 44 12 307 62 48221 422_1 0.2 58 15 149 63 48221 422_1 1 39 6 23550 48222 423_1 0.2 60 12 143 9 48222 423_1 1 43 10 209 57 49345 85_2 0.243 14 242 38 49345 85_2 1 37 5 275 NA 50282 424_1 0.2 75 20 138 19 50282424_1 1 56 9 226 62 51241 426_1 0.2 61 6 144 NA 51241 426_1 1 46 9 26444 51241 425_1 0.2 46 8 164 22 51241 425_1 1 44 4 244 35 51242 428_1 0.257 6 138 30 51242 428_1 1 48 7 290 39 51242 427_1 0.2 40 15 341 NA 51242427_1 1 30 8 286 63 51244 429_1 0.2 46 5 184 25 51244 429_1 1 44 6 283 451245 430_1 0.2 47 7 203 9 51245 430_1 1 37 5 271 29 51358 431_1 0.2 517 265 10 51358 431_1 1 40 4 363 70 51358 432_1 0.2 60 4 202 51 51358432_1 1 37 7 275 NA 51359 433_1 0.2 40 3 238 20 51359 433_1 1 32 3 NA NA51359 434_1 0.2 39 6 424 83 51359 434_1 1 35 6 360 NA 51438 435_1 0.2 7815 144 62 51438 435_1 1 60 14 201 27 51438 436_1 0.2 71 4 125 32 51438436_1 1 54 6 205 71 51953 437_1 0.2 46 6 217 35 51953 437_1 1 37 4 27752 52150 438_1 0.2 67 6 131 39 52150 438_1 1 53 13 177 NA 52549 439_10.2 56 5 162 31 52549 439_1 1 50 10 215 39 52550 440_1 0.2 69 13 137 4052550 440_1 1 50 5 156 53 52551 441_1 0.2 66 3 132 8 52551 441_1 1 49 5169 27 52579 442_1 0.2 38 7 280 60 52579 442_1 1 37 5 257 51 53012 443_10.2 79 10 197 61 53012 443_1 1 65 7 212 36 53013 445_1 0.2 64 6 211 1353013 445_1 1 56 4 264 42 53013 444_1 0.2 68 11 137 33 53013 444_1 1 589 198 35 53014 446_1 0.2 59 6 125 NA 53014 446_1 1 47 3 216 22 53014447_1 0.2 53 2 188 94 53014 447_1 1 51 10 192 47 54198 448_1 0.2 54 15161 66 54198 448_1 1 48 11 243 NA 54199 449_1 0.2 63 12 166 20 54199449_1 1 45 8 185 41 54232 450_1 0.2 84 17 112 67 54232 450_1 1 83 8 15715 54233 451_1 0.2 67 14 118 44 54233 451_1 1 51 8 192 34 54235 452_10.2 50 3 162 NA 54235 452_1 1 42 7 190 NA 54236 453_1 0.2 47 21 234 1754236 453_1 1 42 5 295 NA 54238 454_1 0.2 76 14 85 NA 54238 454_1 1 4812 162 NA 54239 455_1 0.2 62 6 132 69 54239 455_1 1 46 7 149 57 54609456_1 0.2 66 10 130 57 54609 456_1 1 56 11 141 60 54924 457_1 0.2 78 3137 29 54924 457_1 1 61 4 178 25

Example 4—Activity of Oligonucleotides Targeting the SNHG14 Transcriptin the Region Antisense to the UBE3A Pre-mRNA

Oligonucleotides targeting position 55337-136214 of SEQ ID NO: 1 weretested in patient derived human neuronal cell cultures (see protocol in“Materials and methods” section). The oligonucleotides ability to reducethe SNHG14 transcript in the region downstream of SNORD109B (also termedUBE3A suppressor or UBE3A-SUP in the data table). Furthermore, theability to induce UBE3A mRNA re-expression was analyzed.

The oligonucleotides were screened according to the protocol forscreening oligonucleotides in human neuronal cell cultures described inthe section “Materials and methods”—“Screening oligonucleotides in humanneuronal cell cultures—96 well system”.

The results are shown in table 7.

TABLE 7 Oligonucleotide activity in patient derived human neuronal cellcultures. Start SEQ CMP ID Conc % of Mock % of Mock ID NO 1 NO μMUBE3A-SUP sd UBE3A sd 55337 458_1 0.2 64 0 177 6 55337 458_1 1 50 10 2339 55338 459_1 0.2 48 1 186 6 55338 459_1 1 44 9 213 NA 59565 460_1 0.266 4 110 24 59565 460_1 1 66 9 131 23 59574 461_1 0.2 56 5 162 19 59574461_1 1 45 13 149 6 59575 462_1 0.2 56 7 114 84 59575 462_1 1 39 11 10113 59576 463_1 0.2 82 19 52 NA 59576 463_1 1 65 15 95 18 60012 464_1 0.247 5 129 71 60012 464_1 1 41 3 160 64 60298 465_1 0.2 49 7 206 95 60298465_1 1 37 9 222 44 60448 466_1 0.2 47 7 130 NA 60448 466_1 1 33 8 16731 60821 467_1 0.2 87 1 73 NA 60821 467_1 1 62 18 101 3 61925 468_1 0.2108 19 105 19 61925 468_1 1 95 17 101 19 62287 469_1 0.2 62 8 180 5762287 469_1 1 48 5 196 38 62422 470_1 0.2 71 2 130 20 62422 470_1 1 57 9116 18 62443 471_1 0.2 51 2 NA NA 62443 471_1 1 43 2 160 34 64113 472_10.2 95 4 83 22 64113 472_1 1 76 14 74 36 64461 473_1 0.2 79 23 141 2264461 473_1 1 59 12 279 53 64462 474_1 0.2 80 12 138 3 64462 474_1 1 8415 202 3 65272 475_1 0.2 77 3 104 2 65272 475_1 1 75 23 113 10 66840476_1 0.2 67 5 86 5 66840 476_1 1 72 10 100 12 67426 477_1 0.2 62 15 1018 67426 477_1 1 65 13 170 52 68194 478_1 0.2 53 10 109 6 68194 478_1 159 4 178 7 68328 479_1 0.2 74 6 94 2 68328 479_1 1 79 16 111 38 68805480_1 0.2 58 15 157 63 68805 480_1 1 49 2 190 26 68921 481_1 0.2 58 7210 58 68921 481_1 1 55 10 281 NA 70133 482_1 0.2 50 9 149 6 70133 482_11 54 8 247 41 72377 483_1 0.2 44 2 143 NA 72377 483_1 1 52 6 195 3772378 484_1 0.2 47 12 111 8 72378 484_1 1 56 3 201 NA 72826 485_1 0.2 5412 116 0 72826 485_1 1 64 13 172 1 72861 486_1 0.2 52 9 93 6 72861 486_11 54 6 167 16 72887 487_1 0.2 55 3 128 5 72887 487_1 1 59 4 193 24 73474488_1 0.2 55 10 132 20 73474 488_1 1 55 5 202 56 73992 489_1 0.2 60 7146 17 73992 489_1 1 67 7 197 31 74791 490_1 0.2 42 5 167 65 74791 490_11 46 6 277 19 74851 491_1 0.2 69 14 78 1 74851 491_1 1 73 6 114 11 74853492_1 0.2 64 6 84 1 74853 492_1 1 68 5 136 25 75840 493_1 0.2 40 10 90 675840 493_1 1 61 8 155 32 75841 494_1 0.2 65 10 131 30 75841 494_1 1 574 119 16 76238 495_1 0.2 70 9 109 41 76238 495_1 1 50 8 156 22 76254496_1 0.2 67 13 134 34 76254 496_1 1 55 7 201 NA 76811 497_1 0.2 83 7134 41 76811 497_1 1 77 8 148 32 77114 498_1 0.2 59 2 128 13 77114 498_11 64 10 206 NA 80468 499_1 0.2 55 2 105 34 80468 499_1 1 61 6 151 4281047 500_1 0.2 103 17 80 6 81047 500_1 1 143 25 122 7 82233 501_1 0.257 NA 104 NA 82233 501_1 1 61 3 199 39 84166 502_1 0.2 49 6 89 0 84166502_1 1 57 5 115 NA 85392 503_1 0.2 61 6 90 14 85392 503_1 1 62 8 118 1586974 504_1 0.2 73 7 82 4 86974 504_1 1 79 3 104 19 87728 505_1 0.2 7914 76 2 87728 505_1 1 80 19 97 35 87810 506_1 0.2 69 9 101 20 87810506_1 1 73 6 155 2 88417 507_1 0.2 45 NA 116 3 88417 507_1 1 61 14 168 688991 508_1 0.2 51 6 113 20 88991 508_1 1 59 2 154 31 90228 509_1 0.2 656 76 10 90228 509_1 1 62 7 118 4 90474 510_1 0.2 71 7 83 14 90474 510_11 81 3 125 NA 91625 511_1 0.2 57 17 105 3 91625 511_1 1 65 11 150 NA91885 512_1 0.2 57 5 105 1 91885 512_1 1 66 7 155 30 92976 513_1 0.2 676 136 44 92976 513_1 1 68 11 138 38 94304 514_1 0.2 81 11 110 7 94304514_1 1 87 6 153 28 94528 515_1 0.2 48 5 128 6 94528 515_1 1 55 3 191 2595653 516_1 0.2 57 3 108 7 95653 516_1 1 62 3 131 16 96751 517_1 0.2 639 90 19 96751 517_1 1 62 4 106 NA 97636 518_1 0.2 49 5 107 14 97636518_1 1 44 9 137 NA 98480 519_1 0.2 55 1 106 NA 98480 519_1 1 54 5 11223 98481 520_1 0.2 55 2 116 6 98481 520_1 1 62 4 129 6 99646 521_1 0.274 10 105 1 99646 521_1 1 87 13 119 27 100334 522_1 0.2 49 7 157 28100334 522_1 1 57 2 120 37 101110 523_1 0.2 51 10 96 10 101110 523_1 172 14 114 25 101898 524_1 0.2 85 11 79 3 101898 524_1 1 93 21 92 46102558 525_1 0.2 82 9 104 8 102558 525_1 1 86 18 104 30 103589 526_1 0.285 17 114 14 103589 526_1 1 94 39 126 6 104309 527_1 0.2 63 11 148 2104309 527_1 1 70 26 155 NA 105686 528_1 0.2 66 11 91 24 105686 528_1 166 14 140 36 107972 529_1 0.2 84 15 109 15 107972 529_1 1 94 14 127 24108257 530_1 0.2 63 7 114 19 108257 530_1 1 67 12 141 40 109407 531_10.2 84 24 87 16 109407 531_1 1 82 11 127 26 110210 532_1 0.2 72 12 91 14110210 532_1 1 80 14 122 40 110768 533_1 0.2 67 8 126 16 110768 533_1 187 21 176 45 111811 534_1 0.2 77 2 98 17 111811 534_1 1 74 6 143 14111812 535_1 0.2 64 4 97 0 111812 535_1 1 77 3 136 37 112149 536_1 0.273 2 63 2 112149 536_1 1 77 18 127 36 112150 537_1 0.2 76 6 78 8 112150537_1 1 90 29 91 11 112945 538_1 0.2 69 4 121 2 112945 538_1 1 83 14 10239 113533 539_1 0.2 95 17 85 2 113533 539_1 1 91 27 87 17 114274 540_10.2 89 11 103 17 114274 540_1 1 87 26 132 20 114495 541_1 0.2 76 5 88 1114495 541_1 1 83 15 120 6 114831 542_1 0.2 59 3 76 4 114831 542_1 1 743 104 4 115355 543_1 0.2 66 8 91 9 115355 543_1 1 74 16 110 NA 116105544_1 0.2 55 12 77 NA 116105 544_1 1 74 6 110 8 116106 545_1 0.2 58 1896 9 116106 545_1 1 66 8 130 10 117096 546_1 0.2 69 9 118 20 117096546_1 1 65 4 146 NA 117189 547_1 0.2 69 6 98 9 117189 547_1 1 74 11 14625 117476 548_1 0.2 59 4 87 5 117476 548_1 1 65 3 104 10 118293 549_10.2 55 8 92 3 118293 549_1 1 66 10 105 24 118294 550_1 0.2 55 18 90 4118294 550_1 1 72 21 119 5 118756 551_1 0.2 60 13 86 18 118756 551_1 188 24 120 26 119621 552_1 0.2 77 21 117 4 119621 552_1 1 102 19 146 NA120655 553_1 0.2 55 9 124 19 120655 553_1 1 57 7 185 14 123733 554_1 0.274 6 87 14 123733 554_1 1 77 4 127 4 124163 555_1 0.2 89 12 117 46124163 555_1 1 67 20 152 13 125512 556_1 0.2 70 5 114 26 125512 556_1 169 11 119 47 126882 557_1 0.2 78 15 106 8 126882 557_1 1 84 10 113 33127105 558_1 0.2 71 7 91 13 127105 558_1 1 68 5 108 28 127809 559_1 0.259 4 74 NA 127809 559_1 1 58 7 101 26 129020 560_1 0.2 82 11 103 39129020 560_1 1 77 9 103 27 129205 561_1 0.2 75 24 78 16 129205 561_1 189 11 102 23 129928 562_1 0.2 57 0 98 21 129928 562_1 1 63 9 107 18130020 563_1 0.2 65 5 85 9 130020 563_1 1 65 3 145 12 130884 564_1 0.281 24 117 31 130884 564_1 1 83 4 139 17 130886 565_1 0.2 80 8 103 13130886 565_1 1 69 7 122 11 131404 566_1 0.2 79 4 85 3 131404 566_1 1 807 116 24 132514 567_1 0.2 71 8 98 28 132514 567_1 1 69 9 97 29 133367568_1 0.2 78 9 88 16 133367 568_1 1 91 17 88 32 136198 569_1 0.2 88 5 872 136198 569_1 1 81 6 109 35

Example 5—Activity of Oligonucleotides Targeting the SNHG14 Transcriptin the Region Downstream of SNORD109B and Upstream of the RegionAntisense to the UBE3A Pre-mRNA

Oligonucleotides targeting position 5224-51257 of SEQ ID NO: 1 weretested in patient derived human neuronal cell cultures (see protocol in“Materials and methods” section). The oligonucleotides ability to reducethe SNHG14 transcript in the region downstream of SNORD109B (also termedUBE3A suppressor or UBE3A-SUP in the data table. Furthermore, theability to induce UBE3A mRNA re-expression was analyzed.

The oligonucleotides were screened according to the protocol forscreening oligonucleotides in human neuronal cell cultures described inthe section “Materials and methods” “Screening oligonucleotides in humanneuronal cell cultures—96 well system” with the following modifications:

UBE3a-Sense Primer

Using commercially available primers and probe from ThermoFisher:Hs00166580_m1 amplifying a 94 bp sequence in position 838 of refseq IDNM_000462.3.

Each plate include PBS controls (instead on a non-targetingologinucleotide) and a positive control oligonucleotide CMP ID NO:271_1, resulting in up-regulation of UBE3A mRNA. The additional controloligonucleotides were not included.

Data are presented as average % expression relative to PBS controlsacross all plates and normalized to the positive control oligonucleotideto manage plate to plate variation in efficacy levels. The results areshown in table 8.

TABLE 8 Oligonucleotide activity in patient derived human neuronal cellcultures. Start SEQ CMP Conc % of Mock % of Mock ID NO 1 ID NO μMUBE3A-SUP sd UBE3A sd 5224 169_2 7.5 μM 49 4 209 9 5224 169_3 7.5 μM 475 282 5 5224 169_4 7.5 μM 57 14 202 12 5224 169_5 7.5 μM 84 36 148 45224 169_6 7.5 μM 42 1 285 16 5224 169_7 7.5 μM 52 6 233 27 5224 169_87.5 μM 51 7 278 11 5224 169_9 7.5 μM 51 4 228 20 5224 169_10 7.5 μM 7817 143 5 5224 169_11 7.5 μM 74 15 146 2 5224 169_12 7.5 μM 47 1 277 265224 169_13 7.5 μM 56 23 244 42 5224 169_14 7.5 μM 74 16 141 1 5224169_15 7.5 μM 95 32 122 13 5224 169_16 7.5 μM 44 4 276 23 5224 169_177.5 μM 85 5 118 5 5224 169_18 7.5 μM 75 18 131 4 5224 169_19 7.5 μM 9518 126 11 5224 169_20 7.5 μM 61 12 169 20 5224 169_21 7.5 μM 79 18 156 35224 169_22 7.5 μM 63 14 173 16 5224 169_23 7.5 μM 43 2 233 27 5224169_24 7.5 μM 56 1 183 9 5224 169_25 7.5 μM 48 0 220 24 5224 169_26 7.5μM 41 1 244 39 5224 169_27 7.5 μM 55 16 260 42 5224 169_28 7.5 μM 48 1265 65 5224 169_29 7.5 μM 56 2 197 18 5224 169_30 7.5 μM 57 12 189 125224 169_31 7.5 μM 53 4 196 9 5224 169_32 7.5 μM 50 1 220 3 5224 169_337.5 μM 64 19 227 8 5224 169_34 7.5 μM 58 4 193 10 5224 169_35 7.5 μM 452 229 3 5224 169_36 7.5 μM 44 6 262 14 5224 169_37 7.5 μM 55 2 180 215224 169_38 7.5 μM 75 22 158 13 5224 169_39 7.5 μM 76 15 159 17 5224169_40 7.5 μM 60 18 232 31 5224 169_41 7.5 μM 46 3 230 10 5224 169_427.5 μM 47 3 240 11 5224 169_43 7.5 μM 48 9 273 30 5224 169_44 7.5 μM 8332 196 11 5224 169_45 7.5 μM 69 4 185 20 5224 169_46 7.5 μM 45 9 256 35224 169_47 7.5 μM 41 2 304 4 5224 169_48 7.5 μM 44 1 260 16 5224 169_497.5 μM 38 1 245 32 5224 169_50 7.5 μM 35 2 314 28 5224 169_51 7.5 μM 415 281 5 5224 169_52 7.5 μM 36 1 282 1 5224 169_53 7.5 μM 38 7 301 7 5224169_54 7.5 μM 36 3 304 6 5224 169_55 7.5 μM 52 5 246 23 5224 169_56 7.5μM 33 15 302 15 5224 169_57 7.5 μM 34 16 273 16 5784 570_1 7.5 μM 47 0274 7 5784 570_2 7.5 μM 47 8 232 8 5784 570_3 7.5 μM 55 25 280 54 5784570_4 7.5 μM 61 11 235 54 5784 570_5 7.5 μM 72 10 198 30 5784 570_6 7.5μM 66 8 244 50 5784 570_7 7.5 μM 42 1 284 13 5784 570_8 7.5 μM 43 6 25711 5784 570_9 7.5 μM 32 9 242 30 5785 571_1 7.5 μM 40 1 269 35 5785571_2 7.5 μM 42 3 187 6 5785 571_3 7.5 μM 46 6 242 8 5785 571_4 7.5 μM37 4 282 19 5785 571_5 7.5 μM 48 16 296 2 5785 571_6 7.5 μM 37 6 274 105785 571_7 7.5 μM 39 1 260 8 5785 571_8 7.5 μM 35 1 252 3 5785 571_9 7.5μM 30 5 297 10 5786 572_1 7.5 μM 34 4 279 29 5786 572_2 7.5 μM 63 10 1524 5786 572_3 7.5 μM 39 0 280 42 5786 572_4 7.5 μM 40 1 283 14 5786 572_57.5 μM 38 6 310 11 5786 572_6 7.5 μM 33 1 316 18 5786 572_7 7.5 μM 35 1318 11 5786 572_8 7.5 μM 47 9 310 19 5786 572_9 7.5 μM 31 7 321 12 8116573_1 7.5 μM 39 8 316 28 8116 573_2 7.5 μM 49 15 305 41 8116 573_3 7.5μM 46 13 308 3 8116 573_4 7.5 μM 39 3 332 6 8116 573_5 7.5 μM 34 6 27812 8116 573_6 7.5 μM 42 1 285 10 8116 573_7 7.5 μM 38 0 289 33 8116573_8 7.5 μM 40 4 311 20 8116 573_9 7.5 μM 57 9 315 5 8117 574_1 7.5 μM40 2 291 35 8117 574_2 7.5 μM 42 3 343 18 8117 574_3 7.5 μM 36 6 325 88117 574_4 7.5 μM 38 1 279 15 8117 574_5 7.5 μM 42 6 308 10 8117 574_67.5 μM 47 8 340 11 8117 574_7 7.5 μM 43 0 308 42 8117 574_8 7.5 μM 44 6268 10 8117 574_9 7.5 μM 41 8 241 22 8118 575_1 7.5 μM 47 0 198 28 8118575_2 7.5 μM 83 26 253 31 8118 575_3 7.5 μM 48 4 348 5 8118 575_4 7.5 μM37 2 269 7 8118 575_5 7.5 μM 43 6 258 17 8118 575_6 7.5 μM 50 6 286 38118 575_7 7.5 μM 37 2 331 30 8118 575_8 7.5 μM 47 7 264 1 8118 575_97.5 μM 64 23 243 3 8119 576_1 7.5 μM 47 1 272 14 8119 576_2 7.5 μM 10931 119 3 8119 576_3 7.5 μM 36 3 287 6 8119 576_4 7.5 μM 35 3 285 23 8119576_5 7.5 μM 49 10 222 1 8119 576_6 7.5 μM 79 12 132 10 8119 576_7 7.5μM 76 4 132 3 8119 576_8 7.5 μM 62 1 147 5 8119 576_9 7.5 μM 43 3 230 58120 577_1 7.5 μM 57 3 158 15 8120 577_2 7.5 μM 39 4 279 60 8120 577_37.5 μM 38 1 290 68 8120 577_4 7.5 μM 77 11 148 11 8120 577_5 7.5 μM 31 6272 36 8120 577_6 7.5 μM 38 8 228 32 8120 577_7 7.5 μM 40 8 246 39 8120577_8 7.5 μM 43 11 256 26 8120 577_9 7.5 μM 85 32 109 6 8584 578_1 7.5μM 57 7 199 7 8584 578_2 7.5 μM 40 5 263 3 8584 578_3 7.5 μM 40 2 289 238584 578_4 7.5 μM 43 8 199 16 8584 578_5 7.5 μM 42 1 256 15 8584 578_67.5 μM 42 6 241 10 8584 578_7 7.5 μM 42 5 329 20 8584 578_8 7.5 μM 49 7271 13 8584 578_9 7.5 μM 45 3 222 3 8585 579_1 7.5 μM 45 0 208 8 8585579_2 7.5 μM 51 4 226 6 8585 579_3 7.5 μM 54 5 178 8 8585 579_4 7.5 μM41 4 328 13 8585 579_5 7.5 μM 50 5 272 3 8585 579_6 7.5 μM 86 12 161 08585 579_7 7.5 μM 72 5 155 15 8585 579_8 7.5 μM 57 3 230 14 8585 579_97.5 μM 83 0 123 1 8586 580_1 7.5 μM 37 2 313 13 8586 580_2 7.5 μM 43 1266 3 8586 580_3 7.5 μM 42 5 303 5 8586 580_4 7.5 μM 57 4 225 26 8586580_5 7.5 μM 51 4 228 35 8586 580_6 7.5 μM 44 4 253 15 8586 580_7 7.5 μM50 1 241 10 8586 580_8 7.5 μM 44 0 227 26 8586 580_9 7.5 μM 31 5 323 318587 581_1 7.5 μM 50 6 223 30 8587 581_2 7.5 μM 66 7 199 19 8587 581_37.5 μM 56 8 197 9 8587 581_4 7.5 μM 57 12 270 24 8587 581_5 7.5 μM 51 12259 12 8587 581_6 7.5 μM 39 4 282 2 8587 581_7 7.5 μM 38 11 263 5 8587581_8 7.5 μM 45 10 203 19 8587 581_9 7.5 μM 43 2 234 10 9209 582_1 7.5μM 61 7 225 7 9209 582_2 7.5 μM 46 9 341 36 9209 582_3 7.5 μM 44 9 30638 9209 582_4 7.5 μM 43 1 249 5 9209 582_5 7.5 μM 33 16 306 6 9209 582_67.5 μM 37 8 329 19 9209 582_7 7.5 μM 44 9 289 4 9209 582_8 7.5 μM 39 3314 20 9209 582_9 7.5 μM 41 4 299 25 9210 583_1 7.5 μM 43 5 319 25 9210583_2 7.5 μM 53 9 352 5 9210 583_3 7.5 μM 42 2 362 42 9210 583_4 7.5 μM46 5 225 13 9210 583_5 7.5 μM 39 6 343 21 9210 583_6 7.5 μM 44 9 298 89210 583_7 7.5 μM 37 5 332 9 9210 583_8 7.5 μM 42 6 343 25 9210 583_97.5 μM 36 2 341 9 9211 584_1 7.5 μM 45 5 343 39 9211 584_2 7.5 μM 42 2298 22 9211 584_3 7.5 μM 44 10 321 2 9211 584_4 7.5 μM 50 1 299 5 9211584_5 7.5 μM 44 1 319 25 9211 584_6 7.5 μM 50 6 323 13 9211 584_7 7.5 μM42 4 316 27 9211 584_8 7.5 μM 53 3 217 11 9212 208_2 7.5 μM 44 7 312 269212 208_3 7.5 μM 38 2 331 21 9212 208_4 7.5 μM 47 3 353 11 9212 208_57.5 μM 54 11 348 14 9212 208_6 7.5 μM 51 12 310 8 9212 208_7 7.5 μM 60 9224 11 9213 209_2 7.5 μM 44 12 242 21 9213 209_3 7.5 μM 37 12 335 129213 209_4 7.5 μM 55 7 350 2 9213 209_5 7.5 μM 47 7 337 19 9213 209_67.5 μM 51 8 300 19 9213 209_7 7.5 μM 47 15 342 23 9213 209_8 7.5 μM 4512 289 5 9213 209_9 7.5 μM 41 1 368 37 9213 209_10 7.5 μM 40 4 315 111511 585_1 7.5 μM 41 7 350 12 11511 585_2 7.5 μM 44 4 233 7 11511 585_37.5 μM 40 8 310 31 11511 585_4 7.5 μM 33 8 324 41 11511 585_5 7.5 μM 293 314 23 11511 585_6 7.5 μM 38 4 332 15 11511 585_7 7.5 μM 30 2 315 1511511 585_8 7.5 μM 36 11 328 37 11511 585_9 7.5 μM 39 5 303 49 11512586_1 7.5 μM 60 3 236 5 11512 586_2 7.5 μM 40 9 282 53 11512 586_3 7.5μM 36 1 279 11 11512 586_4 7.5 μM 34 3 288 21 11512 586_5 7.5 μM 30 1270 4 11512 586_6 7.5 μM 29 5 269 24 11512 586_7 7.5 μM 33 4 263 6 11512586_8 7.5 μM 32 4 270 4 11512 586_9 7.5 μM 33 5 310 48 11513 587_1 7.5μM 45 2 237 34 11513 587_2 7.5 μM 44 3 307 4 11513 587_3 7.5 μM 37 1 28524 11513 587_4 7.5 μM 44 1 252 41 11513 587_5 7.5 μM 51 7 220 29 11513587_6 7.5 μM 41 2 262 35 11513 587_7 7.5 μM 39 7 280 21 11513 587_8 7.5μM 48 9 230 11 11513 587_9 7.5 μM 41 5 270 9 11514 588_1 7.5 μM 54 9 20425 11514 588_2 7.5 μM 98 5 143 4 11514 588_3 7.5 μM 55 9 180 1 11514588_4 7.5 μM 113 24 109 17 11514 588_5 7.5 μM 66 26 150 5 11514 588_67.5 μM 74 1 131 1 11514 588_7 7.5 μM 79 4 140 9 11514 588_8 7.5 μM 49 2235 2 11514 588_9 7.5 μM 51 10 281 2 11515 589_1 7.5 μM 61 2 154 9 11515589_2 7.5 μM 70 9 126 12 11515 589_3 7.5 μM 53 3 212 32 11515 589_4 7.5μM 93 14 108 14 11515 589_5 7.5 μM 69 11 191 7 11515 589_6 7.5 μM 53 9183 20 11515 589_7 7.5 μM 45 8 257 4 11515 589_8 7.5 μM 35 5 213 5 11515589_9 7.5 μM 41 2 290 22 13223 236_2 7.5 μM 39 6 286 21 13223 236_3 7.5μM 32 10 256 29 13223 236_4 7.5 μM 37 5 285 12 13223 236_5 7.5 μM 33 8280 19 13223 236_6 7.5 μM 40 16 295 7 13223 236_7 7.5 μM 45 10 254 5013223 236_8 7.5 μM 41 22 306 50 13223 236_9 7.5 μM 32 11 292 47 13223236_10 7.5 μM 31 10 307 3 13223 236_11 7.5 μM 52 32 198 29 13223 236_127.5 μM 31 7 261 18 13223 236_13 7.5 μM 34 3 279 32 13223 236_14 7.5 μM38 0 285 75 13223 236_15 7.5 μM 40 17 307 53 13223 236_16 7.5 μM 41 6321 30 13224 237_2 7.5 μM 49 18 251 38 13224 237_3 7.5 μM 53 14 236 3313224 237_4 7.5 μM 39 0 283 26 13224 237_5 7.5 μM 43 2 243 2 13224 237_67.5 μM 39 10 265 48 13224 237_7 7.5 μM 50 3 302 19 13224 237_8 7.5 μM 467 327 43 13224 237_9 7.5 μM 38 9 287 12 13224 237_10 7.5 μM 35 6 248 3513224 237_11 7.5 μM 41 1 259 24 13224 237_12 7.5 μM 33 6 303 35 13224237_13 7.5 μM 26 4 265 53 13224 237_14 7.5 μM 30 8 321 15 13224 237_157.5 μM 33 11 315 24 13224 237_16 7.5 μM 36 11 292 19 13225 239_2 7.5 μM35 16 291 30 13225 239_3 7.5 μM 40 15 311 42 13225 239_4 7.5 μM 81 6 14416 13225 239_5 7.5 μM 90 16 127 11 13225 239_6 7.5 μM 49 29 282 3 13225239_7 7.5 μM 35 4 296 23 13225 239_8 7.5 μM 40 1 292 48 13225 239_9 7.5μM 36 1 318 44 13225 239_10 7.5 μM 49 NA 304 NA 13225 239_11 7.5 μM 45NA 258 NA 13225 239_12 7.5 μM 43 1 285 1 13225 239_13 7.5 μM 31 1 308 3113225 239_14 7.5 μM 41 8 253 6 13225 239_15 7.5 μM 28 3 291 16 13225239_16 7.5 μM 29 3 314 14 13226 590_1 7.5 μM 34 1 283 18 13226 590_2 7.5μM 49 7 213 17 13226 590_3 7.5 μM 40 1 274 51 13226 590_4 7.5 μM 36 1300 2 13226 590_5 7.5 μM 37 3 280 36 13226 590_6 7.5 μM 38 2 204 1713226 590_7 7.5 μM 38 5 245 16 13226 590_8 7.5 μM 30 6 219 34 13226590_9 7.5 μM 33 1 269 2 13226 590_10 7.5 μM 33 2 258 49 13226 590_11 7.5μM 48 17 297 31 13226 590_12 7.5 μM 33 4 317 65 13226 590_13 7.5 μM 35 7337 43 13226 590_14 7.5 μM 25 1 306 22 13226 590_15 7.5 μM 30 5 299 215113 591_1 7.5 μM 43 3 313 14 15113 591_2 7.5 μM 52 2 295 24 15114592_1 7.5 μM 53 2 232 17 15114 592_2 7.5 μM 39 1 309 23 15114 592_3 7.5μM 46 1 278 12 15114 592_4 7.5 μM 36 1 328 13 15114 592_5 7.5 μM 49 9295 40 15114 592_6 7.5 μM 46 3 297 10 15114 592_7 7.5 μM 75 21 160 2315114 592_8 7.5 μM 41 10 325 23 15114 592_9 7.5 μM 55 15 265 3 15115241_2 7.5 μM 66 18 168 2 15115 241_3 7.5 μM 51 15 265 11 15115 241_4 7.5μM 49 4 239 7 15115 241_5 7.5 μM 52 11 314 20 15115 241_6 7.5 μM 41 13307 7 15115 241_7 7.5 μM 38 6 344 33 15115 241_8 7.5 μM 39 10 329 915115 241_9 7.5 μM 50 11 321 32 15115 241_10 7.5 μM 48 9 316 1 15563593_1 7.5 μM 38 10 282 14 15563 593_2 7.5 μM 31 5 279 16 15563 593_3 7.5μM 34 7 281 16 15563 593_4 7.5 μM 32 16 318 2 15563 594_1 7.5 μM 40 2320 21 15563 594_2 7.5 μM 54 7 237 14 15563 594_3 7.5 μM 35 6 300 4515563 594_4 7.5 μM 37 7 254 6 15564 596_1 7.5 μM 47 7 225 35 15564 596_27.5 μM 49 2 184 14 15564 596_3 7.5 μM 34 8 271 18 15564 596_4 7.5 μM 458 277 29 15564 595_1 7.5 μM 42 4 254 6 15564 595_2 7.5 μM 36 9 277 3515564 595_3 7.5 μM 40 8 295 31 15564 595_4 7.5 μM 45 5 173 20 15566597_1 7.5 μM 48 6 296 22 15566 597_2 7.5 μM 44 12 293 8 15566 597_3 7.5μM 41 6 318 23 15566 597_4 7.5 μM 60 9 340 72 15567 38_3 7.5 μM 41 3 30614 15567 38_4 7.5 μM 45 1 303 48 15567 38_5 7.5 μM 39 15 292 28 1556738_6 7.5 μM 46 12 261 40 15567 598_1 7.5 μM 42 2 257 31 15567 598_2 7.5μM 41 12 272 46 15567 598_3 7.5 μM 54 9 281 29 15567 598_4 7.5 μM 45 8307 6 15568 599_1 7.5 μM 47 3 326 68 15568 599_2 7.5 μM 60 14 307 3015568 599_3 7.5 μM 50 8 274 24 15568 599_4 7.5 μM 45 6 250 12 15568600_1 7.5 μM 37 6 251 1 15568 600_2 7.5 μM 45 11 267 15 15568 600_3 7.5μM 44 5 278 1 15568 600_4 7.5 μM 41 10 265 5 15569 601_1 7.5 μM 42 12271 18 15569 601_2 7.5 μM 38 6 269 24 15569 601_3 7.5 μM 39 4 260 3415569 601_4 7.5 μM 56 8 146 1 15570 244_2 7.5 μM 46 1 338 6 15570 244_37.5 μM 47 0 275 47 15570 244_4 7.5 μM 47 8 281 67 15570 244_5 7.5 μM 418 258 52 15570 39_2 7.5 μM 53 4 339 25 15570 39_3 7.5 μM 65 5 200 1715570 39_4 7.5 μM 47 7 321 6 15570 39_5 7.5 μM 46 3 289 20 15571 602_17.5 μM 34 5 278 29 15571 602_2 7.5 μM 39 8 254 37 15571 602_3 7.5 μM 4110 266 23 15571 602_4 7.5 μM 42 8 256 40 15571 40_2 7.5 μM 58 0 325 415571 40_3 7.5 μM 58 2 326 35 15571 40_4 7.5 μM 54 1 306 3 15571 40_57.5 μM 44 2 322 4 15571 40_6 7.5 μM 43 4 293 17 15571 40_7 7.5 μM 53 7343 20 15571 40_8 7.5 μM 52 1 337 17 15572 604_1 7.5 μM 58 1 289 3 15572604_2 7.5 μM 63 12 230 5 15572 604_3 7.5 μM 57 3 306 23 15572 604_4 7.5μM 46 6 324 4 15572 603_1 7.5 μM 60 7 339 31 15572 603_2 7.5 μM 70 0 27919 15572 603_3 7.5 μM 59 9 290 48 15572 603_4 7.5 μM 85 11 123 24 15573605_1 7.5 μM 56 5 288 3 15573 605_2 7.5 μM 58 4 286 6 15573 605_3 7.5 μM59 3 261 9 15573 605_4 7.5 μM 69 24 328 17 15573 606_1 7.5 μM 50 4 28219 15573 606_2 7.5 μM 112 NA 133 NA 15573 606_3 7.5 μM 55 22 254 4315573 606_4 7.5 μM 107 59 116 2 15574 607_1 7.5 μM 56 2 337 31 15574607_2 7.5 μM 59 1 254 10 15574 607_3 7.5 μM 53 0 295 26 15574 607_4 7.5μM 48 3 268 15 25248 608_1 7.5 μM 86 7 189 5 25248 608_2 7.5 μM 102 13136 3 25248 608_3 7.5 μM 54 17 280 12 25248 608_4 7.5 μM 71 8 219 3125248 608_5 7.5 μM 59 20 179 16 25248 608_6 7.5 μM 71 2 198 0 25248608_7 7.5 μM 47 3 230 21 25248 608_8 7.5 μM 55 12 287 13 25248 608_9 7.5μM 66 19 297 18 25249 609_1 7.5 μM 58 19 264 7 25249 609_2 7.5 μM 88 6156 5 25249 609_3 7.5 μM 76 19 140 13 25249 609_4 7.5 μM 50 15 185 625249 609_5 7.5 μM 95 29 139 1 25249 609_6 7.5 μM 86 15 126 7 25249609_7 7.5 μM 72 9 174 1 25249 609_8 7.5 μM 64 3 189 18 25249 609_9 7.5μM 77 12 223 35 25250 610_1 7.5 μM 55 17 233 7 25250 610_2 7.5 μM 52 15233 9 25250 610_3 7.5 μM 77 5 151 11 25250 610_4 7.5 μM 48 0 242 2125250 610_5 7.5 μM 59 8 234 0 25250 610_6 7.5 μM 59 12 208 23 25250610_7 7.5 μM 69 7 216 5 25250 610_8 7.5 μM 70 16 211 2 25250 610_9 7.5μM 77 22 157 19 25251 611_1 7.5 μM 43 4 306 10 25251 611_2 7.5 μM 43 1300 36 25251 611_3 7.5 μM 43 17 306 6 25251 611_4 7.5 μM 40 1 320 3725251 611_5 7.5 μM 48 9 273 7 25251 611_6 7.5 μM 51 2 302 26 25251 611_77.5 μM 40 8 326 8 25251 611_8 7.5 μM 55 10 330 17 25251 611_9 7.5 μM 403 297 11 25252 612_1 7.5 μM 58 9 219 5 25252 612_2 7.5 μM 54 9 282 425252 612_3 7.5 μM 56 13 265 35 25252 612_4 7.5 μM 81 16 239 51 25252612_5 7.5 μM 57 2 234 25 25252 612_6 7.5 μM 76 18 221 8 25252 612_7 7.5μM 45 7 285 11 25252 612_8 7.5 μM 50 8 231 4 25252 612_9 7.5 μM 51 3 30517 29636 271_1 7.5 μM 35 4 345 29 29636 271_1 7.5 μM 32 6 383 31 29636271_1 7.5 μM 42 7 292 13 29636 271_1 7.5 μM 40 1 309 41 29636 271_1 7.5μM 41 10 339 17 29636 271_1 7.5 μM 35 8 306 40 29636 271_1 7.5 μM 33 1320 12 29636 271_1 7.5 μM 43 1 347 7 29636 271_1 7.5 μM 36 2 339 1929636 271_1 7.5 μM 36 1 315 5 29636 271_1 7.5 μM 41 1 326 16 29636 271_17.5 μM 38 2 344 1 29636 271_1 7.5 μM 34 6 341 8 29636 271_1 7.5 μM 42 9320 1 29636 271_1 7.5 μM 31 8 344 37 29636 271_1 7.5 μM 44 2 335 1129636 271_1 7.5 μM 32 0 316 17 29636 271_1 7.5 μM 43 11 323 2 29636271_1 7.5 μM 35 7 340 2 29636 271_1 7.5 μM 43 1 340 8 29636 271_1 7.5 μM33 4 296 27 29636 271_1 7.5 μM 38 5 334 4 29636 271_1 7.5 μM 36 4 341 2229636 271_1 7.5 μM 48 4 334 3 29636 271_1 7.5 μM 36 8 303 13 29636 271_17.5 μM 36 0 343 7 29636 271_1 7.5 μM 39 1 326 1 29636 271_1 7.5 μM 38 2346 14 29636 271_1 7.5 μM 32 0 332 11 29636 271_1 7.5 μM 39 4 330 2329636 271_1 7.5 μM 39 7 346 33 29636 271_1 7.5 μM 40 1 329 14 29636271_1 7.5 μM 34 6 316 38 29636 271_1 7.5 μM 33 4 317 14 29636 271_1 7.5μM 41 6 328 11 29636 271_1 7.5 μM 45 2 345 3 29636 271_1 7.5 μM 37 1 3303 29636 271_1 7.5 μM 45 7 322 18 29636 271_1 7.5 μM 36 3 334 13 29636271_1 7.5 μM 33 8 333 3 29636 271_1 7.5 μM 35 10 321 43 29636 271_1 7.5μM 41 3 323 18 29636 271_1 7.5 μM 39 8 354 39 29636 271_1 7.5 μM 35 2327 23 30599 613_1 7.5 μM 73 29 172 22 30599 613_2 7.5 μM 87 40 114 930599 613_3 7.5 μM 59 23 168 23 30599 613_4 7.5 μM 43 15 281 31 30599613_5 7.5 μM 51 3 271 28 30600 614_1 7.5 μM 56 11 179 22 30600 614_2 7.5μM 96 40 100 7 30600 614_3 7.5 μM 41 7 246 27 30600 614_4 7.5 μM 47 19283 14 30600 614_5 7.5 μM 52 21 209 16 30600 615_1 7.5 μM 61 19 197 1230600 615_2 7.5 μM 45 11 287 25 30600 615_3 7.5 μM 102 NA 115 NA 30600615_4 7.5 μM 72 NA 170 NA 30600 615_5 7.5 μM 95 NA 138 NA 30601 285_27.5 μM 83 NA 165 NA 30601 285_3 7.5 μM 124 NA 111 NA 30601 285_4 7.5 μM69 NA 183 NA 30601 285_5 7.5 μM 47 23 211 7 30601 285_6 7.5 μM 46 12 1836 30601 617_1 7.5 μM 67 26 190 19 30601 617_2 7.5 μM 74 35 137 6 30601617_3 7.5 μM 51 16 211 4 30601 617_4 7.5 μM 65 22 142 11 30601 617_5 7.5μM 43 8 298 26 30601 616_1 7.5 μM 50 22 181 12 30601 616_2 7.5 μM 37 13276 33 30601 616_3 7.5 μM 38 16 264 9 30601 616_4 7.5 μM 43 NA 304 NA30601 616_5 7.5 μM 50 NA 229 NA 30602 619_1 7.5 μM 90 43 131 22 30602619_2 7.5 μM 78 40 138 2 30602 619_3 7.5 μM 66 22 123 8 30602 619_4 7.5μM 100 43 96 5 30602 619_5 7.5 μM 75 17 157 5 30602 618_1 7.5 μM 46 16226 12 30602 618_2 7.5 μM 68 NA 151 NA 30602 618_3 7.5 μM 52 4 207 1830602 618_4 7.5 μM 57 12 223 2 30602 618_5 7.5 μM 54 2 211 3 30603 620_17.5 μM 106 23 110 16 30603 620_2 7.5 μM 48 10 243 18 30603 620_3 7.5 μM53 1 174 32 30603 620_4 7.5 μM 81 0 138 15 30603 620_5 7.5 μM 56 5 218 930604 621_1 7.5 μM 39 4 304 10 30604 621_2 7.5 μM 35 7 311 3 30604 621_37.5 μM 67 18 142 8 30604 621_4 7.5 μM 34 6 273 21 30604 621_5 7.5 μM 365 266 18 30605 622_1 7.5 μM 42 1 242 28 30605 622_2 7.5 μM 31 10 300 830605 622_3 7.5 μM 35 3 319 11 30605 622_4 7.5 μM 37 4 281 5 30605 622_57.5 μM 39 5 306 11 30606 623_1 7.5 μM 47 3 287 1 30606 623_2 7.5 μM 7423 166 7 30606 623_3 7.5 μM 82 1 149 8 30606 623_4 7.5 μM 66 9 135 830606 623_5 7.5 μM 78 7 128 12 30608 624_1 7.5 μM 84 13 185 25 30608624_2 7.5 μM 35 2 245 9 30608 624_3 7.5 μM 31 3 267 9 30608 624_4 7.5 μM39 16 257 13 30608 624_5 7.5 μM 34 3 283 4 30666 625_1 7.5 μM 45 5 28639 30666 625_2 7.5 μM 39 3 280 13 30666 625_3 7.5 μM 40 10 258 9 30666625_4 7.5 μM 41 14 234 39 30666 625_5 7.5 μM 42 5 293 26 30666 625_6 7.5μM 44 0 284 25 30666 625_7 7.5 μM 46 3 271 4 30666 625_8 7.5 μM 47 5 25617 30666 625_9 7.5 μM 40 7 302 2 30667 626_1 7.5 μM 38 1 279 10 30667626_2 7.5 μM 39 21 329 22 30667 626_3 7.5 μM 59 12 265 65 30667 626_47.5 μM 39 5 318 25 30667 626_5 7.5 μM 36 2 302 33 30667 626_6 7.5 μM 366 273 34 30667 626_7 7.5 μM 30 0 299 29 30667 626_8 7.5 μM 35 4 277 4330667 626_9 7.5 μM 32 3 275 22 30668 627_1 7.5 μM 71 3 131 11 30668627_2 7.5 μM 49 4 226 30 30668 627_3 7.5 μM 64 5 147 8 30668 627_4 7.5μM 52 6 176 9 30668 627_5 7.5 μM 78 14 108 3 30668 627_6 7.5 μM 40 1 18323 30668 627_7 7.5 μM 85 8 116 2 30668 627_8 7.5 μM 45 1 128 7 30668627_9 7.5 μM 42 5 215 36 30669 628_1 7.5 μM 90 11 120 15 30669 628_2 7.5μM 73 12 124 4 30669 628_3 7.5 μM 88 2 115 4 30669 628_4 7.5 μM 54 4 19018 30669 628_5 7.5 μM 64 1 138 3 30669 628_6 7.5 μM 62 4 138 11 30669628_7 7.5 μM 55 1 138 13 30669 628_8 7.5 μM 62 1 140 5 30669 628_9 7.5μM 79 10 134 22 30711 629_1 7.5 μM 42 1 252 47 30711 629_2 7.5 μM 40 2295 30 30711 629_3 7.5 μM 46 1 302 78 30711 629_4 7.5 μM 41 3 260 1630711 629_5 7.5 μM 41 1 284 3 30711 629_6 7.5 μM 43 0 262 1 30711 629_77.5 μM 43 3 278 65 30711 629_8 7.5 μM 53 5 234 24 30711 629_9 7.5 μM 374 289 1 30711 629_10 7.5 μM 47 6 292 6 30711 629_11 7.5 μM 50 5 224 2030712 630_1 7.5 μM 44 2 282 22 30712 630_2 7.5 μM 45 6 297 23 30712630_3 7.5 μM 46 2 272 10 30713 631_1 7.5 μM 45 2 294 10 30713 631_2 7.5μM 42 0 285 14 30713 631_3 7.5 μM 38 3 319 21 30713 631_4 7.5 μM 43 3282 4 30713 631_5 7.5 μM 54 2 173 17 30713 631_6 7.5 μM 37 0 315 1030713 631_7 7.5 μM 40 4 317 2 30713 631_8 7.5 μM 44 1 275 5 30713 631_97.5 μM 47 2 233 8 30713 631_10 7.5 μM 108 18 101 3 30714 632_1 7.5 μM 484 210 4 30714 632_2 7.5 μM 53 5 256 5 30714 632_3 7.5 μM 60 5 224 1930714 632_4 7.5 μM 89 12 117 11 30714 632_5 7.5 μM 39 6 312 6 30714632_6 7.5 μM 40 2 278 31 30714 632_7 7.5 μM 86 1 160 21 30714 632_8 7.5μM 57 17 278 40 30714 632_9 7.5 μM 51 7 236 13 30715 304_2 7.5 μM 53 5206 18 30715 304_3 7.5 μM 70 11 142 24 30715 304_4 7.5 μM 88 1 120 1030715 304_5 7.5 μM 82 15 123 7 30715 304_6 7.5 μM 43 4 264 12 30715304_7 7.5 μM 41 5 266 49 30715 304_8 7.5 μM 43 1 291 12 30715 304_9 7.5μM 36 3 285 18 30715 304_10 7.5 μM 42 1 280 40 33376 633_1 7.5 μM 53 1234 50 33376 633_2 7.5 μM 45 5 301 7 33376 633_3 7.5 μM 53 7 263 1733376 633_4 7.5 μM 53 4 229 22 33376 633_5 7.5 μM 43 3 264 36 33376633_6 7.5 μM 53 5 247 12 33376 633_7 7.5 μM 49 6 289 6 33376 633_8 7.5μM 64 11 238 24 33376 633_9 7.5 μM 63 2 249 28 33377 634_1 7.5 μM 57 9250 14 33377 634_2 7.5 μM 53 10 265 3 33377 634_3 7.5 μM 48 2 275 1033377 634_4 7.5 μM 39 6 287 12 33377 634_5 7.5 μM 49 1 255 22 33377634_6 7.5 μM 51 2 291 15 33377 634_7 7.5 μM 47 5 297 16 33377 634_8 7.5μM 42 9 311 14 33377 634_9 7.5 μM 47 5 271 23 33378 635_1 7.5 μM 56 11257 3 33378 635_2 7.5 μM 56 5 213 23 33378 635_3 7.5 μM 61 8 215 8 33378635_4 7.5 μM 58 15 232 16 33378 635_5 7.5 μM 48 3 316 20 33378 635_6 7.5μM 59 5 262 30 33378 635_7 7.5 μM 55 7 287 15 33378 635_8 7.5 μM 42 1284 3 33378 635_9 7.5 μM 40 0 277 23 33379 636_1 7.5 μM 50 2 239 7 33379636_2 7.5 μM 74 16 204 10 33379 636_3 7.5 μM 55 4 201 3 33379 636_4 7.5μM 54 2 238 7 33379 636_5 7.5 μM 52 5 207 43 33379 636_6 7.5 μM 47 3 2496 33379 636_7 7.5 μM 48 5 241 1 33379 636_8 7.5 μM 37 7 304 12 33379636_9 7.5 μM 62 9 245 5 33380 637_1 7.5 μM 39 1 219 25 33380 637_2 7.5μM 59 1 197 11 33380 637_3 7.5 μM 56 1 250 19 33380 637_4 7.5 μM 53 7244 36 33380 637_5 7.5 μM 73 13 297 34 33380 637_6 7.5 μM 65 1 124 1733380 637_7 7.5 μM 74 5 133 5 33380 637_8 7.5 μM 53 2 207 7 33380 637_97.5 μM 54 15 226 26 39806 638_1 7.5 μM 37 7 283 31 39806 638_2 7.5 μM 4911 291 30 39806 638_3 7.5 μM 41 1 270 20 39806 638_4 7.5 μM 42 13 267 939806 638_5 7.5 μM 50 1 184 5 39806 638_6 7.5 μM 38 1 276 15 39806 638_77.5 μM 56 1 292 4 39806 638_8 7.5 μM 41 4 267 11 39806 638_9 7.5 μM 41 4218 33 39807 639_1 7.5 μM 48 15 293 30 39807 639_2 7.5 μM 38 3 269 239807 639_3 7.5 μM 72 5 167 3 39807 639_4 7.5 μM 69 38 242 36 39807639_5 7.5 μM 47 6 303 36 39807 639_6 7.5 μM 53 6 179 5 39807 639_7 7.5μM 51 3 189 8 39807 639_8 7.5 μM 42 3 185 19 39807 639_9 7.5 μM 45 3 20215 39808 640_1 7.5 μM 39 5 265 7 39808 640_2 7.5 μM 37 4 272 56 39808640_3 7.5 μM 38 3 260 17 39808 640_4 7.5 μM 33 4 255 2 39808 640_5 7.5μM 38 3 253 3 39808 640_6 7.5 μM 40 8 216 10 39808 640_7 7.5 μM 39 8 3107 39808 640_8 7.5 μM 41 6 282 21 39808 640_9 7.5 μM 40 5 269 12 44439641_1 7.5 μM 35 6 336 32 44439 641_2 7.5 μM 67 20 161 6 44439 641_3 7.5μM 34 9 317 30 44439 641_4 7.5 μM 62 18 193 9 44439 641_5 7.5 μM 34 4280 3 44439 641_6 7.5 μM 43 1 315 45 44439 641_7 7.5 μM 45 17 307 5344439 641_8 7.5 μM 41 0 294 41 44439 641_9 7.5 μM 37 2 334 43 44440361_2 7.5 μM 36 1 303 15 44440 361_3 7.5 μM 32 3 315 12 44440 361_4 7.5μM 41 1 299 7 44440 361_5 7.5 μM 40 5 295 6 44440 361_6 7.5 μM 40 2 29630 44440 361_7 7.5 μM 39 1 300 55 44440 361_8 7.5 μM 45 6 285 45 44440361_9 7.5 μM 44 6 321 26 44440 361_10 7.5 μM 46 7 290 18 44441 362_2 7.5μM 50 4 277 4 44441 362_3 7.5 μM 40 6 296 8 44441 362_4 7.5 μM 37 5 34018 44441 362_5 7.5 μM 45 2 266 21 44441 362_6 7.5 μM 39 7 263 0 44441362_7 7.5 μM 41 12 262 36 44441 362_8 7.5 μM 35 13 313 6 44441 362_9 7.5μM 36 8 300 20 44441 362_10 7.5 μM 48 10 293 1 46391 642_1 7.5 μM 51 25278 6 46391 642_2 7.5 μM 46 2 303 4 46391 642_3 7.5 μM 48 3 297 11 46391642_4 7.5 μM 45 11 320 37 46391 642_5 7.5 μM 71 32 303 40 46391 642_67.5 μM 47 15 298 16 46391 642_7 7.5 μM 38 6 277 5 46391 642_8 7.5 μM 383 280 20 46391 642_9 7.5 μM 51 20 285 16 46391 642_10 7.5 μM 32 7 293 2046391 642_11 7.5 μM 42 2 291 2 46391 642_12 7.5 μM 40 3 317 19 46391642_13 7.5 μM 39 11 295 5 46391 642_14 7.5 μM 52 20 295 16 46391 642_157.5 μM 39 8 316 38 46391 642_16 7.5 μM 35 2 294 30 46391 642_17 7.5 μM51 5 292 8 46391 643_1 7.5 μM 39 4 276 16 46392 644_1 7.5 μM 39 0 321 746392 644_2 7.5 μM 46 4 308 4 46392 644_3 7.5 μM 44 1 317 3 46392 644_47.5 μM 38 6 315 11 46392 645_1 7.5 μM 46 5 342 42 46392 645_2 7.5 μM 375 292 25 46392 645_3 7.5 μM 46 16 317 30 46392 645_4 7.5 μM 47 8 381 10246392 645_5 7.5 μM 42 2 269 4 46393 646_1 7.5 μM 49 4 295 2 46393 646_27.5 μM 49 9 304 38 46393 646_3 7.5 μM 44 6 298 50 46393 646_4 7.5 μM 431 296 41 46393 646_5 7.5 μM 35 1 260 3 46393 646_6 7.5 μM 40 2 281 6746393 646_7 7.5 μM 38 1 278 44 46393 646_8 7.5 μM 42 6 262 49 46393646_9 7.5 μM 38 3 289 24 46393 646_10 7.5 μM 38 1 317 4 46393 646_11 7.5μM 42 1 320 34 46393 646_12 7.5 μM 36 5 323 8 46393 646_13 7.5 μM 41 3262 27 46393 646_14 7.5 μM 46 13 315 18 46393 646_15 7.5 μM 42 4 340 2746393 646_16 7.5 μM 45 8 360 14 46393 646_17 7.5 μM 44 1 303 3 46393646_18 7.5 μM 50 2 304 28 46393 646_19 7.5 μM 54 10 217 25 51241 425_27.5 μM 49 12 296 3 51241 425_3 7.5 μM 48 6 297 10 51241 425_4 7.5 μM 525 275 25 51241 425_5 7.5 μM 40 6 284 29 51241 425_6 7.5 μM 39 5 301 2251241 425_7 7.5 μM 39 4 263 13 51241 425_8 7.5 μM 32 5 188 13 51241425_9 7.5 μM 42 5 286 2 51241 425_10 7.5 μM 34 3 165 17

Example 6—Activity of Exon-Exon Spanning Oligonucleotides

Oligonucleotides designed to be complementary across exon-exon junctionsof SNHG14-023 (ENST00000554726) were tested for their ability to reducethe SNHG14 transcript in the region downstream of SNORD109B (also termedUBE3A suppressor or UBE3A-SUP in the data table). Furthermore, theability to induce UBE3A mRNA re-expression was analyzed. Theoligonucleotides primarily span exon2 and exon3 (i.e. are complementaryto a region in exon2 and a region in exon 3).

The oligonucleotides were screened according to the protocol forscreening oligonucleotides in human neuronal cell cultures described inthe section Example 5.

The results are shown in table 9.

TABLE 9 Oligonucleotide activity in patient derived human neuronal cellcultures. CMP ID Conc % of Mock % of Mock NO μM UBE3A-SUP sd UBE3A sd674_1 7.5 μM 47 2 214 12 675_1 7.5 μM 44 6 265 10 676_1 7.5 μM 44 3 28416 677_1 7.5 μM 55 19 351 18 678_1 7.5 μM 41 11 257 1 656_1 7.5 μM 46 3140 19 657_1 7.5 μM 35 7 218 27 658_1 7.5 μM 38 12 253 43 659_1 7.5 μM39 7 274 6 660_1 7.5 μM 38 8 275 29 661_1 7.5 μM 43 13 246 21 662_1 7.5μM 27 10 290 5 663_1 7.5 μM 28 0 287 23 664_1 7.5 μM 27 2 288 14 665_17.5 μM 37 9 321 47 666_1 7.5 μM 54 1 259 10 667_1 7.5 μM 47 8 236 2647_1 7.5 μM 19 3 300 25 648_1 7.5 μM 22 7 320 3 649_1 7.5 μM 34 8 326 2650_1 7.5 μM 44 4 292 7 651_1 7.5 μM 36 5 254 9 652_1 7.5 μM 21 2 314 18653_1 7.5 μM 24 5 299 41 654_1 7.5 μM 31 2 344 41 655_1 7.5 μM 60 9 3013 668_1 7.5 μM 21 3 297 11 669_1 7.5 μM 24 5 296 27 670_1 7.5 μM 30 3274 55 671_1 7.5 μM 27 6 263 35 672_1 7.5 μM 27 6 280 50 673_1 7.5 μM 332 290 19

Example 7—Testing In Vitro Efficacy and Potency of SelectedOligonucleotides

Based on the screenings in examples 2 to 5 above 52 oligonucleotideswere selected for potency and efficacy testing.

The oligonucleotides were screened in human AS patient derived cells asdescribed in the Materials and Method section “Screeningoligonucleotides in human neuronal cell cultures—96 well system” withthe following modifications:

For UBE3a-Sense primer commercially available primers and probe fromThermoFisher: Hs00166580_m1 amplifying a 94 bp sequence in position 838of refseq ID NM_000462.3 were used.

Each plate include PBS controls (instead on a non-targetingoligonucleotide) and the positive control oligonucleotides CMP ID NO:186_1 and 39_1 identified in previous screens were included. Theadditional control oligonucleotides described in the materials andmethod section were not included. Oligonucleotide test concentrationswere from 31.6 μM to 1 nM using a 10 point half-log dilution. Alloligonucleotides were tested in 5 independent experiments in 5 differentweeks. In the data QC process some plates were removed from the analysisif these were obvious outliers e.g. no PCR product detected. After thisfiltration there is a minimum of three independent experiments behindeach the reported values.

The EC50 (UBE3A mRNA re-expression) and IC50 (reduction of the SNHG14transcript in the region downstream of SNORD109B, also termed UBE3Asuppressor or UBE3A-SUP in the data table) were determined after curvefitting using a 4 parameter sigmoidal dose-response model. Fitting wasexecuted using the fit engine available inside the Biobook software byIDBS (XLfit). From the curve-fitting the maximum obtainableup-regulation of UBE3A (UBE3A Max Up) and the maximum obtainableknockdown of UBE3A-SUP (UBE3A-SUP max Kd) were determined. Both areshown as % of control (PBS treated cells). The results are shown intable 10, values are reported as geometric means of each biologicalreplicate.

TABLE 10 Oligonucleotide EC50 and IC 50 values and maximum UBE3Aupregulation and UBE3A suppressor knock down. CMP EC50 IC50 UBE3AUBE3A-SUP ID NO ↑ UBE3A Sd ↓ UBE3A-SUP Sd Max Kd Sd max Kd Sd 586_9 0.020.02 0.01 0.00 329.4 25.5 33.5 3.8 585_1 0.03 0.01 0.03 0.02 301.6 18.331.0 5.3 572_7 0.03 0.00 0.01 0.03 294.1 30.4 31.3 3.5 591_1 0.03 0.020.01 0.00 387.3 46.0 41.4 2.8 585_8 0.04 0.02 0.02 0.01 312.3 23.1 35.23.3 626_7 0.04 0.02 0.02 0.00 362.5 44.6 38.7 3.3 621_2 0.04 0.03 0.020.01 264.5 19.6 24.7 3.9 624_3 0.04 0.03 0.04 0.03 288.1 19.2 29.7 5.2169_52 0.04 0.04 0.02 0.01 303.4 23.1 27.3 1.8 624_5 0.04 0.07 0.01 0.01249.2 16.3 16.4 1.4 586_5 0.04 0.01 0.01 0.00 364.4 43.9 30.4 3.3 626_80.04 0.03 0.01 0.01 338.7 24.0 39.1 2.6 169_50 0.05 0.02 0.02 0.02 280.323.0 28.3 2.4 572_6 0.05 0.01 0.01 0.02 298.5 22.4 36.3 4.0 639_5 0.050.03 0.01 0.00 327.7 22.0 38.2 3.6 592_2 0.05 0.03 0.02 0.05 364.9 27.136.4 3.6 586_8 0.05 0.03 0.02 0.01 366.6 35.1 38.0 3.9 625_6 0.06 0.030.01 0.00 335.5 34.7 32.5 1.9 644_3 0.06 0.04 0.01 0.02 298.5 22.0 25.31.6 586_4 0.06 0.03 0.01 0.01 354.3 31.5 33.0 2.3 642_12 0.06 0.05 0.020.01 289.2 14.8 24.7 3.0 572_5 0.07 0.09 0.02 0.00 312.7 25.9 31.5 3.0592_4 0.07 0.06 0.03 0.01 341.1 31.9 35.7 1.8 622_3 0.07 0.04 0.02 0.01300.9 21.0 27.6 3.6 622_5 0.07 0.01 0.02 0.01 306.2 13.5 24.4 4.0 616_40.07 0.04 0.03 0.02 293.8 17.9 29.1 5.0 304_6 0.08 0.08 0.02 0.00 318.139.2 43.8 3.9 638_8 0.08 0.01 0.01 0.01 354.8 30.6 42.4 4.1 622_4 0.080.07 0.02 0.01 330.3 24.8 29.5 2.4 642_13 0.08 0.07 0.04 0.03 268.4 21.026.8 2.5 573_8 0.08 0.01 0.04 0.02 320.1 34.4 34.3 3.4 241_9 0.09 0.040.04 0.03 352.6 26.4 34.1 2.3 304_10 0.09 0.07 0.03 0.01 289.5 19.9 28.32.8 636_8 0.10 0.08 0.03 0.04 330.8 34.1 53.9 13.4  598_4 0.11 0.06 0.030.04 295.0 15.1 41.3 2.2 586_6 0.11 0.10 0.02 0.02 316.2 21.2 23.8 3.5621_1 0.11 0.21 0.02 0.01 311.9 19.2 27.5 5.2 331_1 0.12 0.02 0.03 0.02293.6 49.0 25.1 5.4 626_9 0.13 0.12 0.02 0.03 302.2 32.6 34.4 2.2 169_560.14 0.18 0.02 0.01 356.5 22.3 26.8 2.2 631_6 0.14 0.30 0.04 0.00 292.925.1 33.5 4.9 186_1 0.16 0.02 0.04 0.05 371.7 70.1 32.5 5.5 611_7 0.160.15 0.02 0.01 369.2 29.3 37.2 3.9 165_1 0.17 0.02 0.07 0.12 266.3 NA26.7 NA 646_16 0.18 0.15 0.03 0.02 306.0  9.0 30.6 2.9 640_4 0.20 0.100.02 0.01 328.4 31.0 40.4 7.0 631_1 0.22 0.07 0.07 0.02 324.6  1.6 47.58.1 590_13 0.23 0.59 0.02 0.02 353.4 22.3 31.8 2.2 172_1 0.24 0.10 0.110.14 254.2 NA 34.2 NA 35_2 0.26 0.02 0.06 0.09 257.9 NA 22.3 NA 425_50.26 0.14 0.08 0.08 317.3 33.9 32.9 2.4 359_1 0.27 0.03 0.03 0.08 260.5NA 31.3 NA 209_1 0.28 0.08 0.03 0.03 339.9 30.6 48.2 11.6  123_1 0.280.13 0.26 0.08 235.9 NA 51.8 NA 361_1 0.29 0.10 0.06 0.02 331.9 17.230.7 6.3 602_1 0.31 0.33 0.15 0.20 340.3 21.7 42.2 5.0 NA 0.44 0.12 0.150.18 251.3 NA 24.6 NA 287_1 0.45 0.09 0.04 0.02 318.1 45.2 28.8 9.3303_1 0.46 0.05 0.09 0.15 259.9 NA 30.9 NA 379_1 0.47 0.02 0.08 0.16247.2 NA 22.5 NA 405_1 0.48 0.42 0.04 0.01 323.0 56.2 32.5 11.9  39_10.51 0.20 0.06 0.06 341.2 30.3 40.4 4.7 206_1 0.52 0.07 0.14 0.31 262.9NA 30.5 NA 155_1 0.53 0.10 NA 0.53 260.8 NA 26.7 NA 362_1 0.57 0.25 0.090.02 328.1 57.3 27.4 8.6 178_1 0.58 0.35 0.11 0.04 334.3 50.8 26.6 8.048_1 0.59 0.02 0.07 0.56 262.7 NA 27.2 NA 200_1 0.62 0.51 0.15 0.06331.0 54.3 33.1 6.2 361_5 0.67 0.18 0.07 0.00 307.1 22.9 32.1 4.5 597_40.67 0.51 0.10 0.06 325.3 17.3 35.3 2.7 85_1 0.68 0.06 0.28 0.41 255.5NA 35.1 NA 278_1 0.69 0.67 0.08 0.09 313.8 33.4 27.2 4.6 271_1 0.69 0.000.03 0.65 247.3 NA 24.0 NA 403_1 0.77 0.57 0.11 0.09 296.4 55.0 28.8 7.0204_1 0.78 0.59 0.05 0.05 316.1 35.5 36.3 7.9 116_1 0.91 0.05 0.09 0.43240.6 NA 31.6 NA 124_1 0.92 0.29 0.55 0.94 190.0 NA 43.9 NA 237_8 0.930.66 0.05 0.03 376.2 32.8 33.6 3.7 378_1 0.95 0.64 0.13 0.09 317.7 30.148.5 6.1 126_2 0.95 0.05 0.12 0.70 219.7 NA 45.0 NA 373_1 1.03 0.63 0.130.08 321.7 38.6 27.5 4.8 641_5 1.16 1.36 0.07 0.06 335.1 28.9 26.6 5.1207_1 1.18 0.58 0.18 0.06 318.5 42.9 44.0 7.2 19_1 1.50 0.19 0.24 1.07261.7 NA 28.4 NA 175_1 1.51 0.42 0.17 0.11 333.5 23.8 29.2 5.2 304_11.55 0.09 0.08 0.11 297.8 26.2 32.5 5.7 399_1 1.86 2.50 0.44 0.26 340.152.2 39.6 4.3 38_1 2.12 0.10 0.34 0.43 257.3 NA 45.1 NA 222_1 2.29 0.750.28 0.12 298.2 34.9 26.8 5.6 187_1 2.30 1.39 1.00 0.91 315.3 38.4 28.66.2 272_1 2.32 1.39 0.24 0.16 330.4 41.2 37.1 6.1 18_1 2.42 0.21 0.242.00 271.0 NA 29.3 NA 118_1 2.78 0.30 0.31 0.07 205.4 NA 40.4 NA 35_12.93 4.94 3.61 1.52 258.4 NA 48.2 NA 233_1 3.14 1.68 0.35 0.16 330.320.1 29.3 5.2 220_1 3.47 0.99 1.02 0.48 315.5 27.4 29.6 7.6 33_1 3.970.41 1.07 NA 265.7 NA 32.2 NA 109_1 4.06 1.45 1.33 0.67 231.7 44.7 39.63.9 40_1 4.17 0.05 0.12 3.74 263.6 NA 38.3 NA 115_1 4.98 0.15 0.25 NA184.2 NA 47.0 NA 161_1 6.55 3.20 1.25 1.24 294.0 24.8 32.1 7.4 105_46.61 1.62 1.38 4.20 NA NA 50.6 NA 19_2 6.66 1.17 3.17 1.52 201.7 NA 57.7NA 104_1 7.75 6.77 1.67 1.05 267.9 25.5 42.5 4.1 18_2 20.00 1.67 3.50 NA245.9 NA 46.4 NA 108_1 20.00 0.61 1.27 NA 219.6 NA 51.2 NA 129_2 20.000.08 1.10 NA 165.8 NA 56.5 NA 141_1 20.00 0.03 0.15 NA 159.0 NA 64.1 NA142_1 20.00 1.04 1.12 NA 133.1 NA 57.6 NA 145_1 20.00 1.30 1.81 NA 139.0NA 56.9 NA

The invention claimed is:
 1. An antisense oligonucleotide whichcomprises a contiguous nucleotide sequence of 10 to 30 nucleotides inlength with at least 98% complementarity to position 30654-30745 of SEQID NO: 1, wherein the oligonucleotide comprises one or more modifiedoligonucleotides.
 2. The oligonucleotide of claim 1, wherein theoligonucleotide comprises a sequence selected from the group consistingof SEQ ID NO: 46, 47, 48, 289, 290, 291, 292, 293, 294, 295, 296, 297,298, 299, 300, 301, 302, 303, 304, 304, 305, 625, 626, 627, 628, 629,630, 631, 632, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743,744, 745, 746, 747, 748, 749, 750, 751, 752, 754, 755, 756, 757, 758,759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 772, 773,774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787,788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801,802, 803, 804, 805, 806, and
 807. 3. The oligonucleotide of claim 1 orclaim 2, wherein the one or more modified nucleosides is a 2′ sugarmodified nucleoside.
 4. The oligonucleotide of claim 3, wherein the oneor more 2′ sugar modified nucleoside is independently selected from thegroup consisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA,2′-O-methoxyethyl-RNA, 2′-amino-DNA, 2′-fluoro-DNA, arabino nucleic acid(ANA), 2′-fluoro-ANA and LNA nucleosides.
 5. The oligonucleotide ofclaim 1 or claim 2, wherein the one or more modified nucleoside is a LNAnucleoside.
 6. The oligonucleotide of claim 1, wherein theoligonucleotide comprises at least one modified internucleoside linkage.7. The oligonucleotide of claim 6, wherein the internucleoside linkageswithin the contiguous nucleotide sequence are phosphorothioateinternucleoside linkages.
 8. The oligonucleotide of claim 1, wherein theoligonucleotide is capable of recruiting RNase H.
 9. The oligonucleotideof any of claims 1, 2, 7 and 8, wherein the oligonucleotide is a gapmer.10. The oligonucleotide of claim 8, wherein the oligonucleotide is agapmer of formula 5′-F-G-F′-3′, where region F and F′ independentlycomprise 1-7 modified nucleosides and G is a region between 6 and 16nucleosides which are capable of recruiting RNaseH.
 11. Theoligonucleotide of claim 1, wherein the oligonucleotide is selected fromthe group consisting of CMP ID NO: 46_1, 47_1, 48_1, 48_2, 48_3, 48_4,48_5, 48_6, 48_7, 289_1, 290_1, 291_1, 292_1, 293_1, 294_1, 295_1,296_1, 297_1, 298_1, 299_1, 300_1, 301_1, 302_1, 303_1, 304_1, 304_2,304_3, 304_4, 304_5, 304_6, 304_7, 304_8, 304_9, 304_11, 304_12, 304_13,304_14, 304_15, 305_1, 625_1, 625_2, 625_3, 625_4, 625_5, 625_6, 625_7,625_8, 625_9, 625_10, 625_11, 625_12, 625_13, 625_14, 626_1, 626_2,626_3, 626_4, 626_5, 626_6, 626_7, 626_8, 626_9, 626_10, 626_11, 626_12,626_13, 626_14, 626_15, 627_1, 627_2, 627_3, 627_4, 627_5, 627_6, 627_7,627_8, 627_9, 627_10, 627_11, 627_12, 627_13, 627_14, 628_1, 628_2,628_3, 628_4, 628_5, 628_6, 628_7, 628_8, 628_9, 628_10, 628_11, 628_12,628_13, 628_14, 629_1, 629_10, 629_11, 629_2, 629_3, 629_4, 629_5,629_6, 629_7, 629_8, 629_9, 629_10, 629_11, 629_12, 629_13, 629_14,629_15, 629_16, 630_1, 630_2, 630_3, 631_1, 631_10, 631_2, 631_3, 631_4,631_5, 631_6, 631_7, 631_8, 631_9, 631_11, 631_12, 631_13, 631_14,631_15, 632_1, 632_2, 632_3, 632_4, 632_5, 632_6, 632_7, 632_8, 632_9,632_10, 632_11, 632_12, 632_13, 632_14, 733_1, 733_2, 733_3, 733_4,733_5, 734_1, 734_2, 734_3, 734_4, 734_5, 735_1, 735_2, 735_3, 735_4,735_5, 736_1, 736_2, 736_3, 736_4, 736_5, 737_1, 737_2, 737_3, 737_4,737_5, 738_1, 738_2, 738_3, 738_4, 738_5, 739_1, 739_2, 739_3, 739_4,739_5, 740_1, 740_2, 740_3, 740_4, 740_5, 741_1, 741_2, 741_3, 741_4,741_5, 742_1, 742_2, 742_3, 742_4, 742_5, 743_1, 743_2, 743_3, 743_4,743_5, 744_1, 744_2, 744_3, 744_4, 744_5, 745_1, 745_2, 745_3, 745_4,745_5, 746_1, 746_2, 746_3, 746_4, 746_5, 747_1, 747_2, 747_3, 747_4,747_5, 748_1, 748_2, 748_3, 748_4, 748_5, 749_1, 749_2, 749_3, 749_4,749_5, 750_1, 750_2, 750_3, 750_4, 750_5, 751_1, 751_2, 751_3, 751_4,751_5, 752_1, 752_2, 752_3, 752_4, 752_5, 753_1, 753_2, 753_3, 753_4,753_5, 754_1, 754_2, 754_3, 754_4, 754_5, 755_1, 755_2, 755_3, 755_4,755_5, 756_1, 756_2, 756_3, 756_4, 756_5, 757_1, 757_2, 757_3, 757_4,757_5, 758_1, 758_2, 758_3, 758_4, 758_5, 759_1, 759_2, 759_3, 759_4,759_5, 760_1, 760_2, 760_3, 760_4, 760_5, 761_1, 761_2, 761_3, 761_4,761_5, 762_1, 762_2, 762_3, 762_4, 762_5, 763_1, 763_2, 763_3, 763_4,763_5, 764_1, 764_2, 764_3, 764_4, 764_5, 765_1, 765_2, 765_3, 765_4,765_5, 766_1, 766_2, 766_3, 766_4, 766_5, 767_1, 767_2, 767_3, 767_4,767_5, 768_1, 768_2, 768_3, 768_4, 768_5, 769_1, 769_2, 769_3, 769_4,769_5, 770_1, 770_2, 770_3, 770_4, 770_5, 771_1, 771_2, 771_3, 771_4,771_5, 772_1, 772_2, 772_3, 772_4, 772_5, 773_1, 773_2, 773_3, 773_4,773_5, 774_1, 774_2, 774_3, 774_4, 774_5, 775_1, 775_2, 775_3, 775_4,775_5, 776_1, 776_2, 776_3, 776_4, 776_5, 777_1, 777_2, 777_3, 777_4,777_5, 778_1, 778_2, 778_3, 778_4, 778_5, 779_1, 779_2, 779_3, 779_4,779_5, 780_1, 780_2, 780_3, 780_4, 780_5, 781_1, 782_1, 782_2, 782_3,782_4, 782_5, 783_1, 783_2, 783_3, 783_4, 783_5, 784_1, 784_2, 784_3,784_4, 784_5, 785_1, 786_1, 786_2, 786_3, 786_4, 786_5, 787_1, 787_2,787_3, 787_4, 787_5, 788_1, 788_2, 788_3, 788_4, 788_5, 789_1, 789_2,789_3, 789_4, 789_5, 790_1, 790_2, 790_3, 790_4, 790_5, 791_1, 791_2,791_3, 791_4, 791_5, 792_1, 792_2, 792_3, 792_4, 792_5, 793_1, 793_2,793_3, 793_4, 793_5, 794_1, 794_2, 794_3, 794_4, 794_5, 795_1, 795_2,795_3, 795_4, 795_5, 796_1, 796_2, 796_3, 796_4, 796_5, 797_1, 797_2,797_3, 797_4, 797_5, 798_1, 798_2, 798_3, 798_4, 798_5, 799_1, 799_2,799_3, 799_4, 799_5, 800_1, 800_2, 800_3, 800_4, 800_5, 801_1, 801_2,801_3, 801_4, 801_5, 802_1, 802_2, 802_3, 802_4, 802_5, 803_1, 803_2,803_3, 803_4, 803_5, 804_1, 804_2, 804_3, 804_4, 804_5, 805_1, 805_2,805_3, 805_4, 805_5, 806_1, 806_2, 806_3, 806_4, 806_5, 807_1, 807_2,807_3, 807_4, 807_5.
 12. A conjugate comprising the oligonucleotide ofany of claims 1, 2 and 8, and at least one conjugate moiety covalentlyattached to said oligonucleotide.
 13. A pharmaceutical compositioncomprising the oligonucleotide of any of claims 1, 2 and 8 and apharmaceutically acceptable diluent, solvent, carrier, salt and/oradjuvant.
 14. An in vivo or in vitro method for inducingubiquitin-protein ligase E3A (UBE3A) expression in a target cell whereexpression of paternal UBE3A is suppressed, said method comprisingadministering an oligonucleotide of claim 1 in an effective amount tosaid cell.
 15. The method according to claim 14, wherein the expressionof UBE3A is increased by at least 40% compared to a control.
 16. Themethod according to claim 14, wherein the level of the SNHG14 transcriptdownstream of SNORD109B is reduced by at least 30% compared to acontrol.
 17. The method according to claim 14, wherein the target cellis a neuronal cell.
 18. The method according to claim 14, wherein theexpression of SNORD115 is not significantly affected compared to acontrol.
 19. A method for treating a disease comprising administering atherapeutically or prophylactically effective amount of anoligonucleotide of claim 1 to a subject suffering from or susceptible toAngelman syndrome.
 20. The oligonucleotide of claim 1 for use in thetreatment of Angelman syndrome.
 21. The oligonucleotide of claim 1,wherein the oligonucleotide comprises SEQ ID NO:
 626. 22. Theoligonucleotide of claim 10, wherein the oligonucleotide comprises CMPID NO: 626_7.
 23. The oligonucleotide of claim 2, wherein theoligonucleotide consists of TTAcActtaattatactTCC (SEQ ID NO: 626) andpharmaceutically acceptable salts thereof, wherein capital lettersrepresent beta-D-oxy LNA nucleosides, lowercase letters represent DNAnucleosides, all LNA C are 5-methyl cytosine, and all internucleosidelinkages are phosphorothioate internucleoside linkages.
 24. Apharmaceutical composition comprising the oligonucleotide of claim 23and a pharmaceutically acceptable diluent, solvent, carrier, salt and/oradjuvant.